Pyrimidine derivative

ABSTRACT

The present invention provides a novel pyrimidine derivative represented by the general formula (1):                    
     (wherein R, R 4  and R 8  are the same as defined in the specification) or pharmaceutically acceptable salt thereof, which possesses an excellent activity for inhibiting the formation of NO (nitrogen oxide) in vivo.

FIELD OF THE INVENTION

The present invention relates to a novel pyrimidine derivative whichinhibits the formation of NO (nitrogen monoxide) in vivo, and relates toagents for curing asthma and atopic dermatis is containing, as theeffective ingredient, said pyrimidine derivative or a salt thereof.

BACKGROUND ART

There have been known that NO (nitrogen monoxide) is generated in vivowhen L-citrulline is formed by oxidation of the constitutional nitrogenatoms in the guanidino moiety of arginine through N-hydroxy-L-arginineintermediate. This reaction proceeds by action of NO synthase(hereinafter referred to as NOS) which acts as a catalyst.

There have been known several types of NOS, thus cNOS (constitutive NOS)which is constitutively existed naturally in the cells, and iNOS(inducible NOS) is synthesized inductively by stimulation of cytokainesor endotoxins [e.g., lipopolysaccharide (LPS)]. Examples of cNOS,includes endothelial cell NOS (eNOS) and nerve cell NOS (nNOS), andexamples of iNOS includes macrophage NOS (mNOS).

Excessive amounts of NO and its metabolic products formed in vivo by theaction of above-mentioned NOS (mainly, iNOS) induce several activities,such as lowering the blood pressure, activation of guanylate cyclase,acceleration of ribosylating adenosine diphosphate (ADP), deactivationof iron-containing enzymes, inhibition of synthesis of proteins andnucleic acids, inhibiting aggregation of platelet, inhibiting adhesionof neutrophil, etc., thus NO takes part in onset of various diseases.

For example, NO has an influence to disturb the native functions of thecells. Therefore, when a certain amount of NO is generated in the cellsdue to postponement of over-manifestation of iNOS, then it is understoodthat NO acts as a disturbance factor to the living body.

The disturbance factor is known to be regarded to various pathemas forexample, septic shock, inflammations, reperfusion disturbance,arteriosclerosis, hypertension and myocarditis which may be occurredrelating to the blood vessels and cardiac system; pneumonia and asthmawhich may be occurred relating to the lung and respiratory system; acuterenal failure and glomerular philitis which may be occurred relating tothe renal system; neurotoxicity, spasm, migraine, hyperesthesia whichmay be occurred relating to the brain and nervus system; mucosaldisturbance, ulcerative colitis and diabetes mellitis which may beoccurred relating to the digestive system; chronic rheumatic arthritisand the like which may be occurred relating to the immunological system.

Asthma is basically occurred due to spasmodic contraction of smoothmuscle of the airway together with inflammation of the airway,deposition of viscous secreta inside of the airway, and edema of theairway mucosa.

There have been proposed several theories relating to pathogenesis ofasthma, e.g., 1) mechanism based on allergy, 2) infections withmicroorganisms, 3) autonomic imbalance, 4) psychoneurotic cause, 5)β-blocking theory, 6) predisposing cause, 7) over response of theairway, 8) a specific mechanism, etc., and among of these theories themechanism based on allergy is considered as the most important cause.

In asthmatic patients, there are two types of symptoms, one of them isan immediate asthmatic response (IAR) in which the asthmatic attack isinduced quickly after the exposure to an antigen, another of them is alate asthmatic response (LAR) in which the asthmatic attack ismanifested slowly thus, several hours after the exposure to an antigen.At present, an agent for inhibiting LAR is particularly desired.

Currently, β-stimulant drugs, steroidal anti-inflammatory drugs aremainly administered to asthmatic patients. However, there are reportedthat asthmatic patients are encountered in high risk to asthmatic deathin case of administered β-stimulant drug in high dosage. As to themechanism of side-effects of β-stimulant drug, the cardiac arrhythmiaand drug tolerance are considered to be the highest possibility.

Additionally, steroidal anti-inflammatory drugs are indeed effective tocure asthmatic symptoms, while they bring serious systemic side-effects.Of cause, certain countermeasures are tried to reduce such side-effectscaused by inhalation type of steroidal drugs. However, similar to oraladministration type drugs, some dangers may be caused to osteoporosisand lowering of lung compliance by such inhalation type drugs. Thus, anydrug being capable of replacing steroidal drugs, or any drug having theability at least to reduce the dosage of the steroidal drugs aredesired.

For the purpose to reduce dosage of steroidal drugs, there are reportedthat mild effects for reducing the dosage can be expected by usingMethotrexate, a gold salt containing drug and cyclosporins. However,these drugs itself have severe side-effects which are different from theside-effects shown by the steroidal drugs. Thus, any drug without havingthese side-effects are desired.

On the other hand, although calcium antagonists may be used for reducingconstriction of the airway, but they show much side-effects and are notpractical. While by using PAF (platelet activating factor) antagonists,there was not reported any preferable results in curing asthmaticdisease.

Under the circumstances, any drug being capable to substitute steroidaldrugs or any drugs having similar effect to steroidal drugs withoutside-effect is desired. That is, any drug effective to patient who issuffering from the disease caused by tolerance to steroidal drug orvicious asthmatic disease such as asthma resistant to steroidal drug isdesired.

It is known that amounts of NO and its derivatives in the exhalation ofbronchial asthmatic patient is found to be increased.

Also, it is understood that NO is closely relates to the constriction ofsmooth muscle of the trachea together with inflammation of the airway,also relates to atopic dermatitis.

With respect to a pyrimidine derivative represented by the generalformula (1) of the present invention, having inhibitory action againstthe effects of NO, the present inventors have made studies onanti-allergic activities, especially on anti-asthmatic effect andanti-atopic dermatitis effect performed thereby. As the result, theinventors have found the facts that, the pyrimidine derivative (1) ofthe present invention is a compound to be substituted for conventionalsteroidal drugs or a compound which is capable to reduce the dosage ofconventional steroidal drugs, for this reason that the pyrimidinederivative (1) possesses activity for inhibiting the generation of NO,especially it performs an excellent effect for curing the late asthmaticresponse (LAR), also possesses an equivalent or higher performance inanti-asthmatic effect and anti-atopic dermatitis, as compared with theactivity shown by conventional steroidal anti-inflammatory drug.

As to the NOS inhibitors to be used for curing the above-mentioneddiseases, there are known, for example L-NMMA(N^(G)-monomethyl-L-arginine), L-NA (N^(G)-nitro-L-arginine), L-AME(L-arginine methyl ester), L-NAME (N^(G)-nitro-L-arginine methyl ester)and the like.

However, administration of these NOS inhitors cannot good enough forcure the above-mentioned various diseases. Under such circumstances,novel compounds having excellent activities for inhibiting the formationof NO in vivo and in case of curing asthma, an agent to be able tosubstitute for steroidal drugs, or an agent having at least effect forsaving the dosage of steroidal drugs is desired.

In JP-A-5-112571, WO 97/11946, WO 95/35298 and JP-A-6-312987, there aredisclosed pyrimidine derivatives similar to the pyrimidine derivatives(1) of the present invention. However, there are not any disclosurerelating to the activity for inhibiting the formation of NO performed bythese pyrimidine derivatives known in these prior art.

DISCLOSURE OF THE INVENTION

In consideration of the above-mentioned facts, the present inventorshave made an extensive research work to solve the above-mentionedsubjects. As the result, the present inventors have found the facts andknowledges that novel pyrimidine derivatives represented by thefollowing general formula (1) and pharmaceutically acceptable saltsthereof possess excellent effects for inhibiting the formation of NO, aswell as having the effects for curing asthma and atopic dermatitis, andfinally the present invention was successfully completed.

[wherein R represents a group of the formula:

(wherein R¹ is a hydrogen atom or a lower alkyl group; R² is a hydrogenatom or a lower alkoxy group; R³ is a hydrogen atom, an alkyl group, alower alkanoyl group, a phenyl group which may have substituentsselected from the group consisting of a lower alkoxy group, a carboxylgroup, a halogen substituted-lower alkyl group and a lower alkyl group,an aralkyl group, a heterocyclic group, a cycloalkyl group, ahydroxy-lower alkyl group, and a lower alkoxy-lower alkyl group; A is anoxygen atom or sulfur atom; further R² and R³ may be combined to eachother to form 5- or 6-membered heterocyclic group; n is 0-2); R⁴ is ahydrogen atom, a lower alkyl group or a lower alkoxy group; R⁸ is ahydrogen atom, a lower alkyl group or a lower alkoxy-lower alkyl group].

In addition to the activity for inhibiting the generation of NO in vivo,the pyrimidine derivative (1) of the present invention possesses theactivities for inhibiting the productions of mediators such as cytokines[e.g., IL-4, IL-5 and IL-8 (Interleukin-4, -5 and -8)], TNF-α (Tumornecrosis factor-α), LT (Leukotrienes), PAF (platelet-activating factor),PGs (prostaglandins), GM-CSF (granulocyte-macrophage colony-stimulatingfactor) and the activity for inhibiting 5-lipoxygenase, thus, thepyrimidine derivative (1) possesses excellent effects for curing variousallergic diseases inflammatory diseases, and cancers.

Furthermore, the pyrimidine derivative (1) possesses permeability to theblood vessels of the airway, and having activity for inhibiting cellularinfiltration into the alveolus, particularly it is excellent for curingbronchial asthma, inhibiting of the late asthmatic response in thebronchial asthma, and for curing vicious asthmatic diseases such assteroidal drug tolerated asthma, and, asthma resistant to steroidaldrug, and for curing atopic dermatitis.

In the present invention, bronchial asthma, allergic rhinitis, atopicdermatitis and allergic dermatitis are exemplified as the allergicdiseases.

The pyrimidine derivatives (1) of the present invention is characterizedby having strong activities for inhibiting the formation of NO, havinglong acting time, good property of translocation in blood, and excellenteffect of selectivity for the organs, further having low toxicity.

The pyrimidine derivative (1) of the present invention orpharmaceutically acceptable salts thereof have excellent activity forinhibiting the generation of NO in vivo. Therefore, the pyrimidinederivatives (1) can be used suitably for curing various diseases whichare caused by excessive amounts of NO and its metabolic products.Examples of diseases are, arthritis, gastritis, glomerular philitis,ulcerative colitis, bronchitis, myocarditis, heart diseases, cardiacishemia, ocular anemia, retinitis, uveitis, diabetes mellitus, septicshock, toxic shock, hypotension, neurogenic degeneration,gastrointestinal disturbances, sunburn, eczematoid dermatitis,psoriasis, adult respiratory distress syndrome (ARDS), atherosclerosis,systemic sclerosis, chronic sclerosis, multiple sclerosing degeneration,Crohn's disease, systemic lupus erythematodes, follicular fibrosis,hypoxia, spam and toxicity caused by hyperbaric oxygen, dementia,Sydenham's chorea, Huntington's disease, muscular atrophic disease,Korsakoff's disease, mental deterdation caused by megaroencephalia,cerebral cell injury and secondary diseases thereby, ishemic cerebraledema, schizophrenia, depression, vertigo, obstructive cerebral bloodvessel malady, spam, headache, pains, tolerance and dependence tomorphine or azepin drugs, Alzheimer's disease, Parkinson's disease,osteoarthritis, viral arthritis, asthma, rheumatic arthritis, chronicarthritis, atopic dermatitis and the like. Particularly, a novelpyrimidine derivative (1) is excellent for curing asthma and atopicdermatitis.

The pyrimidine derivatives (1) of the present invention involvingvarious derivatives as shown below.

(1) A pyrimidine derivative or pharmaceutically acceptable salt thereof,wherein R¹, R², R³, R⁴, R⁸ and n are the same as defined in theabove-mentioned general formula (1); and A is an oxygen atom.

(2) A pyrimidine derivative or pharmaceutically acceptable salt thereof,wherein R¹, R², R³, R⁴, R⁸ and n are the same as defined in theabove-mentioned general formula (1); and A is a sulfur atom.

(3) A pyrimidine derivative or pharmaceutically acceptable salt thereof,wherein R¹, R², R³, R⁴, R⁸ and A are the same as defined in theabove-mentioned general formula (1); and n is 1 to 2.

(4) A pyrimidine derivative or pharmaceutically acceptable salt thereof,wherein R¹, R², R³, R⁴, R⁸ and A are the same as defined in theabove-mentioned general formula (1); and n is 0.

(5) A pyrimidine derivative or pharmaceutically accept able saltthereof, wherein R¹, R², R³, R⁴ and R⁸ are same as defined in theabove-mentioned general formula (1); A is an oxygen atom; and n is 1 to2.

(6) A pyrimidine derivative or pharmaceutically acceptable salt thereof,wherein R¹, R², R³, R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); A is an oxygen atom; and n is 0.

(7) A pyrimidine derivative or pharmaceutically acceptable salt thereof,wherein R¹, R², R³, R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); A is a sulfur atom; and n is 1 to2.

(8) A pyrimidine derivative or pharmaceutically accept able saltthereof, wherein R¹, R², R³, R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); A is a sulfur atom; and n is 0.

(9) A pyrimidine derivative or pharmaceutically accept able saltthereof, wherein R¹, R², R⁴, R⁸, A and n are the same as defined in theabove-mentioned general formula (1); R³ is a hydrogen atom, an alkylgroup, a lower alkanoyl group, a phenyl group which may have thesubstituent(s) selected from the group consisting of a lower alkoxygroup, a carboxyl group, a halogen-substituted-lower alkyl group and alower alkyl group, or a lower alkoxy-lower alkyl group.

(10) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴, R⁸, A and n are the same as defined in theabove-mentioned general formula (1); and R³ is an aralkyl group, aheterocyclic group, a cycloalkyl group, or a hydroxy-lower alkyl group.

(11) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴, R⁸, A and n are the same as defined in theabove-mentioned general formula (1); and R³ is an alkyl group or a loweralkoxy-lower alkyl group.

(12) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴, R⁸, A and n are the same as defined in theabove-mentioned general formula (1); and R³ is an alkyl group.

(13) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴, R⁸, A and n are the same as defined in theabove-mentioned general formula (1); and R³ is a lower alkoxy-loweralkyl group.

(14) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴, R⁸, A and n are the same as defined in theabove-mentioned general formula (1); and R³ is a lower alkyl group or alower alkoxy-lower alkyl group.

(15) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴, R⁸, A and n are the same as defined in theabove-mentioned general formula (1); and R³ is a lower alkyl group.

(16) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴, R⁸ and n are the same as defined in theabove-mentioned general formula (1); A is an oxygen atom; and R³ is ahydrogen atom, an alkyl group, a lower alkanoyl group, a phenyl groupwhich may have the substituent(s) selected from the group consisting ofa lower alkoxy group, a carboxyl group, a halogen substituted-loweralkyl group and a lower alkyl group, or a lower alkoxy-lower alkylgroup.

(17) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴, R⁸ and n are the same as defined in theabove-mentioned general formula (1); A is an oxygen atom; and R³ is anaralkyl group, a heterocyclic group, a cycloalkyl group, or ahydroxy-lower alkyl group.

(18) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴, R⁸ and n are the same as defined in theabove-mentioned general formula (1); A is an oxygen atom; and R³ is analkyl group or a lower alkoxy-lower alkyl group.

(19) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴, R⁸ and n are the same as defined in theabove-mentioned general formula (1); A is an oxygen atom; and R³ is analkyl group.

(20) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴, R⁸ and n are the same as defined in theabove-mentioned general formula (1); A is an oxygen atom; and R³ is alower alkoxy-lower alkyl group.

(21) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴, R⁸ and n are the same as defined in theabove-mentioned general formula (1); A is an oxygen atom; and R³ is alower alkyl group or a lower alkoxy-lower alkyl group.

(22) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴, R⁸ and n are the same as defined in theabove-mentioned general formula (1); A is an oxygen atom; and R³ is alower alkyl group.

(23) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴, R⁸ and n are the same as defined in theabove-mentioned general formula (1); A is a sulfur atom; and R³ is ahydrogen atom, an alkyl group, a lower alkanoyl group, a phenyl groupwhich may have the substituent(s) selected from the group consisting ofa lower alkoxy group, a carboxyl group, a halogen substituted-loweralkyl group and a lower alkyl group, or a lower alkoxy-lower alkylgroup.

(24) A pyrimidine derivative or pharmaceutically acceptable saltsthereof, wherein R¹, R², R⁴, R⁸ and n are the same as defined in theabove-mentioned general formula (1); A is a sulfur atom; and R³ is anaralkyl group, a heterocyclic group, a cycloalkyl group, or ahydroxy-lower alkyl group.

(25) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴, R⁸ and n are the same as defined in theabove-mentioned general formula (1); A is a sulfur atom; and R³ is analkyl group or a lower alkoxy-lower alkyl group.

(26) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴, R⁸ and n are the same as defined in theabove-mentioned general formula (1); A is a sulfur atom; and R³ is analkyl group.

(27) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴, R⁸ and n are the same as defined in theabove-mentioned general formula (1); A is a sulfur atom; and R³ is alower alkoxy-lower alkyl group.

(28) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴, R⁸ and n are the same as defined in theabove-mentioned general formula (1); A is a sulfur atom; and R³ is alower alkyl group or a lower alkoxy-lower alkyl group.

(29) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴, R⁸ and n are the same as defined in theabove-mentioned general formula (1); A is a sulfur atom; and R³ is alower alkyl group.

(30) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); n is 0; A is an oxygen atom; and R³is a hydrogen atom, an alkyl group, a lower alkanoyl group, a phenylgroup which may have the substituent(s) selected from the groupconsisting of a lower alkoxy group, a carboxyl group, a halogensubstituted-lower alkyl group and a lower alkyl group, or a loweralkoxy-lower alkyl group.

(31) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); n is 0; A is an oxygen atom; and R³is an aralkyl group, a heterocyclic group, a cycloalkyl group, or ahydroxy-lower alkyl group.

(32) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); n is 0; A is an oxygen atom; and R³is an alkyl group or a lower alkoxy-lower alkyl group.

(33) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); n is 0; A is an oxygen atom; and R³is an alkyl group.

(34) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); n is 0; A is an oxygen atom; and R³is a lower alkoxy-lower alkyl group.

(35) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); n is 0; A is an oxygen atom; and R³is a lower alkyl group or a lower alkoxy-lower alkyl group.

(36) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); n is 0; A is an oxygen atom; and R³is a lower alkyl group.

(37) A pyrimidine derivatives or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); n is 0; A is a sulfur atom; and R³is a hydrogen atom, an alkyl group, a lower alkanoyl group, a phenylgroup which may have the substituent(s) selected from the groupconsisting of a lower alkoxy group, a carboxyl group, a halogensubstituted-lower alkyl group and a lower alkyl group, or a loweralkoxy-lower alkyl group.

(38) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); n is 0; A is a sulfur atom; and R³is an aralkyl group, a heterocyclic group, a cycloalkyl group, or ahydroxy-lower alkyl group.

(39) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); n is 0; A is a sulfur atom; and R³is an alkyl group or a lower alkoxy-lower alkyl group.

(40) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴, and R⁸ are the same as defined in theabove-mentioned general formula (1); n is 0; A is a sulfur atom; and R³is an alkyl group.

(41) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); n is 0; A is a sulfur atom; and R³is a lower alkoxy-lower alkyl group.

(42) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); n is 0; A is a sulfur atom; and R³is a lower alkyl group or a lower alkoxy-lower alkyl group.

(43) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); n is 0; A is a sulfur atom; and R³is a lower alkyl group.

(44) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); n is 1 to 2; A is an oxygen atom;and R³ is a hydrogen atom, an alkyl group, a lower alkanoyl group, aphenyl group which may have the substituent(s) selected from the groupconsisting of a lower alkoxy group, a carboxyl group, a halogensubstituted-lower alkyl group and a lower alkyl group, or a loweralkoxy-lower alkyl group.

(45) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); n is 1 to 2; A is an oxygen atom;and R³ is an aralkyl group, a heterocyclic group, a cycloalkyl group, ora hydroxy-lower alkyl group.

(46) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); n is 1 to 2; A is an oxygen atom;and R³ is an alkyl group or a lower alkoxy-lower alkyl group.

(47) A pyrimidine derivatives or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); n is 1 to 2; A is an oxygen atom;and R³ is an alkyl group.

(48) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); n is 1 to 2; A is an oxygen atom;and R³ is a lower alkoxy-lower alkyl group.

(49) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); n is 1 to 2; A is an oxygen atom;and R³ is a lower alkyl group or a lower alkoxy-lower alkyl group.

(50) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); n is 1 to 2; A is an oxygen atom;and R³ is a lower alkyl group.

(51) A pyrimidine derivative or pharmaceutically accept able saltthereof, wherein R¹, R², R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); n is 1 to 2; A is a sulfur atom;and R³ is a hydrogen atom, an alkyl group, a lower alkanoyl group, aphenyl group which may have the substituent(s) selected from the groupconsisting of a lower alkoxy group, a carboxyl group, a halogensubstituted-lower alkyl group and a lower alkyl group, or a loweralkoxy-lower alkyl group.

(52) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); n is 1 to 2; A is a sulfur atom;and R³ is an aralkyl group, a heterocyclic group, a cycloalkyl group ora hydroxy-lower alkyl group.

(53) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); n is 1 to 2; A is a sulfur atom;and R³ is an alkyl group or a lower alkoxy-lower alkyl group.

(54) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); n is 1 to 2; A is a sulfur atom;and R³ is an alkyl group.

(55) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); n is 1 to 2; A is a sulfur atom;and R³ is a lower alkoxy-lower alkyl group.

(56) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); n is 1 to 2; A is a sulfur atom;and R³ is a lower alkyl group or a lower alkoxy-lower alkyl group.

(57) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); n is 1 to 2; A is a sulfur atom;and R³ is a lower alkyl group.

(58) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R⁴, R⁸, A and n are the same as defined in theabove-mentioned general formula (1); R² and R³ are combined to eachother to form a 5- or 6-membered heterocyclic group.

(59) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R⁴, R⁸ and n are the same as defined in theabove-mentioned general formula (1); A is an oxygen atom; R² and R³ arecombined to each other to form a 5- or 6-membered heterocyclic group.

(60) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); n is 0; A is an oxygen atom; R² andR³ are combined to each other to form a 5- or 6-membered heterocyclicgroup.

(61) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R⁴ and R⁸ are the same as defined in theabove-mentioned general formula (1); n is 1 to 2; A is an oxygen atom;R² and R³ are combined to each other to form a 5- or 6-memberedheterocyclic group.

(62) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴, R⁸, A and n are the same as defined in theabove-mentioned general formula (1); R³ is an aralkyl group, a pyridylgroup, a cycloalkyl group or a hydroxy-lower alkyl group.

(63) A pyrimidine derivative or pharmaceutically acceptable saltthereof, wherein R¹, R², R⁴, R⁸, A and n are the same as defined in theabove-mentioned general formula (1); R³ is a phenyl-lower alkyl group, apyridyl group, a cycloalkyl group or a hydroxy-lower alkyl group.

Examples of each one of the substituents shown in the above-mentionedgeneral formula (1) are specifically explained as follows.

As to the lower alkyl group, an alkyl group having 1 to 6 carbon atoms,such as methyl, ethyl, butyl, propyl, isopropyl, butyl, t-butyl, pentyland hexyl groups can be exemplified.

As to the alkyl group as defined in R3, in addition to theabove-mentioned alkyl groups, an alkyl group having 1 to 16 carbonatoms, such as heptyl, octyl, nonyl, decyl, undecyl and dodecyl groupscan be exemplified.

As to the lower alkoxy group, an alkoxy group having 1 to 6 carbonatoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy,pentyloxy and hexyloxy groups can be exemplified.

As to the aralkyl group, an aralkyl group having 1 to 6 carbon atoms,such as benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl,4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 1,1-dimethyl-2-phenylethyland 2-methyl-2-phenylpropyl can be exemplified.

As to the cycloalkyl group, a cycloalkyl group having 3 to 8 carbonatoms, such as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl groups can be exemplified.

As to the lower alkanoyl group, a straight chain- or branchedchain-alkanoyl group having 1 to 6 carbon atoms, such as acetyl,propionyl, butyryl, isobutyryl, pentanoyl, t-butylcarbonyl and hexanoylgroups can be exemplified.

As to the hydroxy-lower alkyl group, a hydroxy-lower alkyl group having1 to 6 carbon atoms, such as hydroxymethyl, 2-hydroxyethyl,1,1-dimethyl-2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl,2-hydroxybutyl, 5-hydroxypentyl, 1-hydroxypentyl and 6-hydroxyhexylgroups can be exemplified.

As to the phenyl group which may have as the substituent selected fromthe group consisting of a hydrogen atom, a carboxyl group, a halogensubstituted-lower alkyl group, a lower alkyl group and a lower alkoxygroup, a phenyl group which may have as the substituent selected fromthe group consisting of a hydrogen atom, an alkyl group having 1 to 6carbon atoms, an alkyl group having 1 to 6 carbon atoms with whichhalogen atoms are substituted, an alkoxy group having 1 to 6 carbonatoms and carboxyl group, such as phenyl, carboxyphenyl, tolyl,ethylpheyl, propylphenyl, butylphenyl, hexylphenyl, methoxyphenyl,ethoxyphenyl, butoxyphenyl, hexyloxyphenyl, monochloromethylphenyl,monobromomethylphenyl, monofluoromethylphenyl, dichloromethylphenyl,dibromomethylphenyl, difluoromethylphenyl, trichloromethylphenyl,tribromomethylphenyl, triiodomethylphenyl, trifluoromethylphenyl,4-(1,2-dichloroethyl)phenyl, 2-(3-bromopropyl)phenyl,3-(2,3,4-trifluorobutyl)phenyl and 4-(5-iodohexyl)phenyl groups can beexemplified.

As to the lower alkoxy-lower alkyl group, a lower alkoxy-lower alkylgroup in which each one of the alkoxy moiety and alkyl moietyrespectively having 1 to 6 carbon atoms, such as methoxymethyl,methoxyethyl, methoxybutyl, methyoxyhexyl, ethoxymethyl, propoxyethyl,isopropoxymethyl, methoxypropyl, butoxyethyl, t-butoxyhexyl,pentyloxyethyl, hexyloxymethyl and hexyloxypropyl groups can beexemplified.

Compounds represented by the general formula (1) of the presentinvention can be prepared by various methods, for example, they can beprepared by the following Reaction process step-1 to -10.

Reaction process step-1

(wherein R, R⁴ and R⁸ are the same as defined previously; R⁵ is a loweralkyl group or a phenylalkyl group which may have 1 to 3 substituentsselected from the group consisting of nitro group, an alkoxy group andan alkyl group).

This reaction is carried out by reacting a compound represented by thegeneral formula (2) with a compound represented by the general formula(3) in the absence or presence of a suitable solvent, in the presence ofan acid, to obtain a compound represented by the general formula (1) ofthe present invention.

Examples of the above-mentioned solvent are halogenated hydrocarbonssuch as chloroform, dichloromethane and the like; aromatic hydrocarbonssuch as benzene, toluene and the like; and aprotic polar solvents suchas N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitrileand the like.

Examples of the above-mentioned acid are Lewis acids such as anhydrousaluminum chloride, stannic chloride, titanium tetrachloride, borontrichloride, complex of boron trifluoride-ethyl ether, zinc chloride andthe like; inorganic acids such as phosphoric acid, hydrochloric acid,nitric acid, sulfuric acid and the like; and organic acids such astrichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, aceticacid and the like.

Used ratio of a compound (3) to a compound (2) may be at least anequimolar quantity, preferably 1 to 2 times of the molar quantity. Usedratio of the acid to a compound (2) may be 1 to 50 times of the molarquantity, preferably 1 to 10 times of the molar quantity. The reactionis carried out at room temperature to 200° C., preferably at 100 to 110°C. and is finished in about 1 to 30 hours.

In case of that the terminal group of R is a hydroxyl group, then thereaction may be preferably carried out by protecting the hydroxyl group.After finished Reaction process step-1, said protecting group may beremoved by methods in accordance with Reaction process step-2 and -3 asfollows.

Reaction process step-2

(wherein R⁴ and R⁸ are the same as defined previously).

This reaction is carried out by hydrolyzing a compound (4) obtained byReaction process step-1 to obtain a compound represented by the generalformula (1-a) of the present invention.

The reaction is carried out in a suitable solvent, and in the presenceof a basic compound or acidic compound. Example of the solvent arealcohols such as methanol, ethanol and the like; and ethers such asdimethyl ether, diethyl ether, tetrahydrofuran, dioxane and the like.

Examples of the basic compound are, trialkylamines such astriethylamine, tributylamine and the like; organic basic compounds suchas pyridine, picoline, 1,5-diazabicyclo[4.3.0]nonene-5,1,4-diazabicyclo[2.2.2]-octane, 1,8-diazabicyclo[5.4.0]undecene-7 andthe like; inorganic basic compounds for example, alkali metal hydroxidessuch as sodium hydroxide, potassium hydroxide and the like; alkali metalcarbonates such as sodium carbonate, potassium carbonate and the like;and alkali metal hydrogencarbonates such as sodium hydrogencarbonate,potassium hydrogencarbonate and the like.

Examples of the acidic compound are Lewis acids such as anhydrousaluminum chloride, stannic chloride, titanium tetrachloride, borontrichloride and the like; inorganic acids such as hydrochloric acid,hydrobromic acid, nitric acid, sulfuric acid and the like; organic acidssuch as trichloroacetic acid, trifluoroacetic acid, methanesulfonicacid, acetic acid, formic acid and the like; further acidic typeion-exchange resins can be exemplified.

These basic compound or acidic compound may be used suitably in theratio of 1 to 20 times the molar quantity, preferably 1 to 10 times themolar quantity to a compound (4). The reaction may be carried out at 0to 150° C., preferably at 0° C. to room temperature, for about 1 to 24hours.

Reaction process step-3

(wherein R⁴ and R⁸ are the same as defined previously).

This reaction gives a compound represented by the general formula (1-b)of the present invention by removing t-butyl group, which is aprotecting group for the hydroxyl group, through hydrolysis.

This reaction is carried out in a suitable inert solvent, in thepresence of an acidic compound. Examples of the inert solvent arealcohols such as methanol, ethanol and the like; halogenatedhydrocarbons such as dichloromethane, dichloroethane, chloroform and thelike.

As to the acid, for example Lewis acids such as anhydrous aluminumchloride, stannic chloride, titanium tetrachloride, boron trichlorideand the like; inorganic acids such as hydrochloric acid, hydrobromicacid, nitric acid, sulfuric acid and the like; organic acids such astrichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, aceticacid, formic acid and the like; further acidic type ion-exchange resinscan be mentioned.

The acidic compound is used suitably in a ratio of 1 to 20 times themolar quantity, preferably 1 to 10 times the molar quantity to acompound (5). The reaction may be carried out at 0° C. to 100° C.,preferably at 0° C. to room temperature, for about 1 to 30 hours.

Reaction process step-4

(wherein R⁴ and R⁸ are the same as defined previously).

This reaction gives a compound (2) by reacting a compound (6) withhydrazine (NH₂NH₂.H₂O) or its dihydrochloride or its sulfate in thepresence of acetic acid or a mineral acid. The above-mentioned hydrazinemay be used preferably in an amount of 1 to 2 times the molar quantity,and the reaction may be carried out preferably at room temperature to100° C. Acetic acid or a mineral acid may be used preferably in anamount of 1 to 2 times the molar quantity to the hydrazine.

Reaction process step-5

(wherein R and R⁸ are the same as defined previously; R⁶ is a loweralkyl group).

This reaction gives a compound (6) by reacting an acetonitrilederivative represented by the general formula (7) with a specific ester.

When a formic acid ester is used as the above-mentioned specific ester,then R⁸ is a hydrogen atom. As to the formic acid ester, methyl formate,ethyl formate and the like may be exemplified.

This reaction is carried out in an inert solvent. Examples of the inertsolvent are aromatic hydrocarbons such as benzene, toluene, xylene andthe like; ethers such as diethyl ether, tetrahydrohydrofuran, dioxaneand the like; N,N-dimethylformamide, dimethyl sulfoxide and the like.Used ratio of the ester to a compound (7) may be at least an equimolarquantity, preferably 1.05 to 1.25 times the molar quantity. Generally,the reaction may be carried out preferably under an ice-coolingcondition for about 5 to 20 minutes, next at room temperature for about4 to 15 hours. In order to proceed the reaction sufficiently, thereaction may be carried out preferably in the presence of at least anequimolar quantity of a sodium alkoxide such as sodium methoxide, or ametal hydride such as sodium hydride to the ester.

The reaction product (6) is obtained by adding water to the reactionmixture and separating the aqueous layer, then the pH of the aqueouslayer is controlled to pH 3 to 4 by adding a mineral acid such ashydrochloric acid and to sediment the reaction product (6).

Reaction process step-6

(wherein X is a halogen atom; R⁷ is a lower alkyl group; and R⁴ is thesame as defined previously).

This Reaction process step-6 gives a compound of the general formula (9)by reducing a compound of the general formula (8) by use of ahydrogenation reducing agent, next this compound (9) is reacted with ahalogenating agent to obtain a compound of the general formula (10),further, this compound of the general formula (10) is reacted with acyanide compound to obtain a compound of the general formula (7) whichis the starting material of Reaction process step-3.

The reaction for obtaining a compound (9) from a compound (8) is carriedout in a suitable solvent. Examples of the solvent are ethers such asdiethyl ether, tetrahydrofuran, dioxane, diglyme and the like; aliphatichydrocarbons such as hexane, heptane and the like; aromatic hydrocarbonssuch as benzene, toluene and the like can be mentioned. Further, as tothe hydrogenation reducing agent to be used in this reaction, lithiumaluminum hydride, aluminum hydride, diisopropyl aluminum hydride,lithium borohydride, sodium borohydride-aluminum chloride, diborane andthe like can be exemplified. Used amount of the hydrogenation reducingagent is at least 0.5 time the molar quantity, preferably about 0.6 to1.2 times the molar quantity to a compound (8). The reaction isgenerally carried out under an ice-cooling condition to 100° C.,preferably at 0 to 50° C., and is finished in about 30 minutes to 10hours.

The reaction for obtaining a compound (10) from a compound (9) iscarried out in the absence or presence of a suitable solvent. Examplesof the solvent to be used in this reaction are ethers such as diethylether, tetrahydrofuran, dioxane and the like; halogenated hydrocarbonssuch as methylene chloride, chloroform, dichloroethane and the like;aromatic hydrocarbons such as benzene, toluene and the like. Further,examples of the halogenating agent to be used in this reaction arethionyl halides such as thionyl chloride, thionyl bromide and the like;hydrogen halides such as hydrogen chloride, hydrogen bromide, hydrogeniodide and the like; phosphorus halides such as phosphorus trichloride,phosphorus tribromide and the like. Used amount of the halogenatingagent to a compound (9) may be at least an equimolar quantity,preferably 1 to 1.3 times the molar quantity. The reaction is carriedout under an ice-cooling condition to at 100° C., preferably at about 0to 50° C., and is finished in about 30 minutes to 5 hours.

The reaction for obtaining a compound (7) from a compound (10) iscarried out in a suitable solvent. Examples of the solvent to be used inthis reaction are lower alcohols such as methanol, ethanol, propanol andthe like; aprotic polar solvents such as acetone, N,N-dimethylformamide(DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide (HMPA)and the like; and mixed solvents of water with these solvents. Further,examples of the cyanide compound to be used in this reaction arepotassium cyanide, sodium cyanide, silver cyanide, copper cyanide,calcium cyanide and the like can be exemplified. Used amount of thecyanation agent to a compound (10) may be at least an equimolarquantity, preferably 1 to 1.3 times the molar quantity. The reaction iscarried out at room temperature to 150° C., preferably at roomtemperature to 100° C., and is finished in about 1 to 24 hours.

Reaction process step-7

(wherein R⁴ and R⁷ are the same as defined previously). This reactiongives a compound represented by the general formula (8), which is thestarting material of the above-mentioned Reaction process step-6, bysubjecting a compound represented by the general formula (11) to aconventional esterification.

The above-mentioned esterification is carried out for example in thepresence of a catalyst, by reacting a compound (11) with an alcoholrepresented by the formula:

R⁷—OH

(wherein R⁷ is the same as defined previously).

As to the catalyst to be used in the esterification, a conventionalcatalyst for esterification can be used, concretely inorganic acids suchas hydrogen chloride, concentrated sulfuric acid, phosphoric acid, apolyphosphoric acid, boron trifluoride, perchloric acid and the like;organic acids such as trifluoroacetic acid, trichloromethanesulfonicacid, naphthalenesulfonic acid, p-toluenesulfonic acid, benzenesulfonicacid, ethanesulfonic acid and the like; acid anhydrides such astrichloromethanesulfonic acid anhydride, trifluorometanesulfonic acidanhydride and the like; and catalysts such as thionyl chloride can beexemplified. Additionally, cation-exchange resins (acid type) can alsobe used. The above-mentioned esterification is carried out in theabsence or presence of a suitable solvent. Examples of the solvent to beused are any conventional solvent being used for an esterification canbe used, for example aromatic hydrocarbons such as benzene, toluene,xylene and the like; halogenated hydrocarbons such as dichloromethane,dichloroethane, chloroform and the like; ethers such as diethyl ether,tetrahydrofuran, dioxane and the like can be mentioned. Used ratio ofthe acid to a compound (11) may be an equimolar quantity to 100 timesthe molar quantity, preferably 10 to 30 times the molar quantity. Thereaction may be carried out at −20° C. to 200° C., preferably at 0 to150° C.

Additionally, a compound (8) can be obtained by a method for reacting analkali metal salt (for example, sodium salt, potassium salt and thelike) of a compound (11) with a halide compound represented by thegeneral formula:

R⁷—X

(wherein R⁷ and X are the same as defined previously); by a method ofreacting a compound (11) with a diazoalkane such as diazomethane,diazoethane, diazopropane or the like; or by a method for reacting acompound (11) with an alcohol represented by the general formula:

R⁷—OH

(wherein R⁷ is the same as defined previously) after conversion of thecarboxy group of compound (11) into a reactive group (for example, acidchloride, amide or acid anhydride). These esterification can be carriedout in accordance with a conventional method.

Reaction process step-8

(wherein X and R⁴ are the same as defined previously).

This reaction gives a compound represented by the general formula (11),which is the starting material of the above-mentioned Reaction processstep-7, by reacting a benzoic acid derivative represented by the generalformula (12) with a phenylthio derivative represented by the generalformula (13). The reaction is carried out in a suitable solvent in thepresence of a basic compound such as sodium hydroxide, potassiumhydroxide or the like. Examples of the solvent to be used are aproticpolar solvents such as N,N-dimethylformamide (DMF),N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), hexamethylphosphorictriamide (HMPA) and the like.

Used ratio of a compound (13) to a compound (12) may be at least anequimolar quantity, preferably slightly excessive amount may be used.Further, in order to form a compound (11) and a salt of compound (12),at least 2 times the molar quantity, preferably a slightly excessiveamount of the basic compound may be used to a compound (12). Thereaction is generally carried out at room temperature to 180° C., and isfinished in about 30 minutes to 24 hours.

Reaction process step-9

(wherein R and R⁵ are the same as defined previously).

This reaction is a method for obtaining a compound (3) which is thestarting material of Reaction process step-1.

A carboxylic acid represented by the general formula (14) is reactedwith a condensing agent of 1,1′-carbonylbis-1H-imidazole (15), after thereaction, a compound (16) is added without separating the formed productand a compound (3) of the starting material of Reaction process step-1is obtained.

As to the solvent to be used, inert solvents such as tetrahydrofuran(THF), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO),acetonitrile, toluene, 1,2-dimethoxyethane and the like can beexemplified.

Used ratio of 1,1′-carbonylbis-1H-imidazole and a compound (15) may beat least equimolar quantities, preferably 1 to 2 times the molarquantities to a compound (14).

The reaction is generally carried out at room temperature to 180° C.,and is continued for 1 to 6 hours after addition of1,1′-carbonylbis-1H-imidazole (15) to a compound (14), further adding acompound (16), the reaction is finished in about 1 to 30 hours.

Reaction process step-10

(wherein R, R¹, R², R₃, R⁵, A and X are the same as defined previously).

This reaction is a different method for obtaining the starting material(3) of Reaction process step-1. Thus, after addition of sodium hydrideto a compound (17), then thus obtained product is reacted with acompound (18) to obtain the starting material (3) of Reaction processstep-1.

Examples of the solvent to be used in this reaction are, pyridine;halogenated hydrocarbons such as chloroform, dichloromethane and thelike; aromatic hydrocarbons such as benzene, toluene and the like;aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitrile and the like.

Used amount of sodium hydride to a compound (17) may be at least anequimolar quantity, preferably 1 to 5 times of the molar quantity.Further, used amount of a compound (18) to a compound (17) may be atleast an equimolar quantity, preferably 1 to 2 times the molar quantity.Reaction is carried out at 0 to 150° C., and is finished in about 1 to24 hours.

Pyrimidine derivatives represented by the general formula (1) of thepresent invention involve tautomers (1-A) and (1-B) as shown in thefollowing equilibrium formula (i):

(wherein R, R⁴ and R⁸ are the same as defined previously).

Pyrimidine derivatives (1) of the present invention may contain opticalisomers, syn-isomers and anti-isomers. These isomers can be separated byconventional separating methods, for example methods of opticalresolution, methods by using enzymes and the like.

Pyrimidine derivative (1) of the present invention can be used generallyin various forms of common pharmaceutical preparations. Thepharmaceutical preparations are prepared by formulating with commonlyemployed diluents or excipients, such as fillers, extenders, binders,wetting agents, disintegrants, surfactants, lubricants and the like. Thepharmaceutical preparations can be shaped into various forms andselected upon the curing purposes, thus typical examples of the formsare tablets, pills, powders, liquid medicines, supensions, emulsions,granules, capsules, suppositories, injection preparations (liquids,suspensions and the like), also they can be formulated as medicines forexternal use such as lotions, creams, ointments and the like.

In case of shaping the pharmaceutical preparations into the form oftablets, any known carriers which are used widely in this field can beapplied. Examples of the carriers are, excipients such as lactose, whitesugar, sodium chloride, glucose, urea, starch, calcium carbonate,kaolin, crystalline cellulose, silicic acid and the like; binders suchas water, ethanol, propanol, simple syrup, glucose solution, starchsolution, gelatin solution, carboxymethyl cellulose, shellac, methylcellulose, calcium phosphate, polyvinylpyrrolidone and the like;disintegrators such as dry starch, sodium alginate, agar powder,laminarin powder, sodium hydrogencarbonate, calcium carbonate,polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate,monoglyceride of stearic acid, starch, lactose and the like;disintegration inhibitors such as white sugar, stearin, cacao butter,hydrogenated oils and the like; absorption accelerators such asquaternary ammonium bases, sodium lauryl sulfate and the like;humectants such as glycerin, starch and the like; adsorbents such asstarch, lactose, kaolin, bentonite, colloidal silicic acid and the like;and lubricants such as refined talc, stearic acid, boric acid powder,polyethylene glycols and the like can be mentioned. Further, in case ofnecessity, the tablets can be prepared in the form of common coatedtablets, for example, sugar-coated tablets, gelatin film-coated tablets,enteric film coated tablets, film-coated tablets, or in the form ofdouble-layer tablets, multiple-layers tablets and the like.

In case of shaping the pharmaceutical preparations into the form ofpills, any known carriers which are used widely in this field can beapplied. Examples of the carriers are, excipients such as glucose,lactose, starch, cacao butter, hydrogenated vegetable oils, kaolin, talcand the like; binders such as arabic gum powder, tragacanth gum powder,gelatin, ethanol and the like; and disintegrators such as laminarin,agaragar and the like.

In case of shaping the pharmaceutical preparations into the form ofsuppositories, any known carriers which are used widely in this fieldcan be applied. Examples of the carriers are, polyethylene glycols,cacao butter, higher alcohols, esters of higher alcohols, gelatin,semi-synthesized glycerides and the like.

In case of shaping the pharmaceutical preparations into the form ofinjection preparations, solutions, emulsions and suspensions aresterilized and preferably they may be formulated as isotonic to theblood. In preparing the injection preparations as in the form ofsolutions, emulsions or suspensions, any known diluents which are usedwidely in this field can be applied. Examples of the diluents are water,ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylatedisostearyl alcohol, fatty acid esters of polyoxyethylene sorbitan andthe like. In case of prepare the injection preparations as isotonic tothe blood, sufficient amount of sodium chloride, glucose or glycerin maybe contained therein. Additionally, a dissolving additive, a buffersolution, an analgesic agent and the like which are commonly used may becontained therein. In case of necessity, a coloring agent, apreservatives, a purfume, a flavoring agent, a sweetening agent andother medicines may be contained therein.

In case of shaping the pharmaceutical preparations into external usepreparations, for example as in the form of pastes, creams and gels,then diluents such as white petrolatum, paraffin, glycerin, cellulosederivatives, polyethylene glycols, silicones, bentonite and the like canbe used.

The amount of pyrimidine derivative (1) or salt thereof of the presentinvention to be contained in pharmaceutical preparation is notparticularly restricted and can be selected from a wide range, generallythe amount may be selected within the range of 1 to 70% by weight in thewhole composition of the preparation.

Method for administering pharmaceutical preparations according to thepresent invention is not particularly restricted, each one of thesepharmaceutical preparation forms are administered according to the ageof patient, the distinction of sex and other conditions, the degree ofdisease conditions and others. For example, tablets, pills liquids,suspensions, emulsions, granules and capsules are administered orally.

An injection preparation is intravenously administered singly or incombination with common auxiliary solutions such as glucose solution andamino acid solution. In case of necessity, it is singly administeredintramuscularly, intradermally, subcutaneously or intraperitoneally.

A suppository is administered intrarectally. Further, an externalpreparation, such as lotion, cream, ointment and the like is coated onthe diseased part.

Dosage of the above-mentioned pharmaceutical preparation is suitablyselected depend upon the method of administration, the age of patient,the distinction of sex, and other conditions, as well as the degree ofdisease and other conditions, and generally the amount of pyrimidinederivative or salt thereof of the present invention may be in an amountof 1 to 100 mg, preferably 5 to 20 mg per 1 kg of the body weight perday, and such dosage can be administered dividedly in 2 to 4 times aday.

EXAMPLES

The present invention will be explained in detail by illustratingReference examples and Examples as follows.

Reference Example 1

[Synthesis of 4-nitrobenzyl 4-ethoxyacetoacetate]

Under an ice-cooling condition, ethoxyacetic acid (0.95 ml) was added toa suspension of tetrahydrofuran (10 ml), containing1,1′-carbonylbis-1H-imidazole (1.95 g), and the mixture was stirred atroom temperature for 4 hours. Next, to this reaction mixture were addedmagnesium 4-nitrobenzyl malonate (6.01 g) and N,N-dimethylformamide (10ml), and this mixture was stirred at room temperature. 18 Hours afterthe reaction, ethyl acetate was added to the reaction mixture, and thesolid matters deposited were removed by filtration, then 10%hydrochloric acid was added to the thus obtained filtrate and themixture was shaken. The organic layer separated from this mixture waswashed with an aqueous solution saturated with sodium hydrogencarbonate,and an aqueous solution saturated with sodium chloride in this order,the washed organic layer was dried by adding anhydrous sodium sulfatethereto. After removal of the anhydrous sodium sulfate by filtration,the solvent was removed by distillation, there was obtained theabove-mentioned desired compound (2.21 g).

¹H-NMR (CDCl₃) δ: 1.22 (t, J=7 Hz, 3H), 3.55 (q, J=7 Hz, 2H), 3.66 (s,2H), 4.09 (s, 2H), 5.28 (s, 2H), 7.54 (d, J=8.9 Hz, 2H), 8.24 (d, J=8.9Hz, 2H).

Reference Example 2

[Synthesis of 4-nitrobenzyl 4-t-butoxyacetoacetate]

Reactions were carried out similar to those of used in Reference example1, except that the same molar quantity of t-butoxyacetic acid was usedin place of ethoxyacetic acid, there was obtained the above-mentioneddesired compound.

¹H-NMR (CDCl₃) δ: 1.20 (s, 9H), 3.68 (s, 2H), 4.00 (s, 2H), 5.27 (s,2H), 7.54 (d, J=8.6 Hz, 2H), 8.23 (d, J=8.6 Hz, 2H).

Reference Example 3

[Synthesis of 4-nitrobenzyl β-oxo-tetrahydro-2-furanpropionate]

Reactions were carried out similar to those of used in Reference example1, except that the same molar quantity of tetrahydro-2-francarboxylicacid was used in place of ethoxyacetic acid, there was obtained theabove-mentioned desired compound.

¹H-NMR (CDCl₃) δ: 1.85-2.10 (m, 3H), 2.15-2.28 (m, 1H), 3.68-3.69 (m,2H), 3.87-3.95 (m, 2H), 4.35-4.40 (m, 1H), 5.27 (s, 2H), 7.54 (d, J=8.8Hz. 2H), 8.23 (d, J=8.8 Hz, 2H).

Reference Example 4

[Synthesis of 4-nitrobenzyl β-oxo-tetrahydro-2-pyranpropionate]

Reactions were carried out similar to those of used in Reference example1, except that the same molar quantity of tetrahydro-2-pyranncarboxylicacid was used in place of ethoxyacetic acid, there was obtained theabove-mentioned desired compound.

¹H-NMR (CDCl₃) δ: 1.40-1.59 (m, 4H), 1.90-2.16 (m, 2H), 3.39-3.49 (m,1H), 3.66 (d, J=16.5 Hz, 1H), 3.74 (d, J=16.8 Hz, 1H), 3.85 (dd, J=2.3Hz, 10.9 Hz, 1H), 4.01 (d, J=12.2 Hz. 1H), 5.27 (s, 2H), 7.54 (d, J=8.6Hz, 2H), 8.23 (d, J=8.9 Hz, 2H).

Reference Example 5

[Synthesis of 4-nitrobenzyl 5-ethoxy-3-oxopentanate]

Reactions were carried out similar to those of used in Reference example1, except that the same molar quantity of 3-ethoxypropionic acid wasused in place of ethoxyacetic acid, there was obtained theabove-mentioned desired compound.

¹H-NMR (CDCl₃) δ: 1.17 (t, J=7 Hz, 3H), 2.78 (t, J=6 Hz, 2H), 3.48 (q,J=7 Hz, 2H), 3.62 (s, 2H), 3.69 (t, J=6 Hz, 2H), 5.27 (s, 2H), 7.54 (d,J=9 Hz, 2H), 8.24 (d, J=9 Hz, 2H).

Reference Example 6

[Synthesis of 4-nitrobenzyl 5-methoxy-3-oxopentanate]

Reactions were carried out similar to those of used in Reference Example1, except that the same molar quantity of 3-methoxypropionic acid wasused in place of ethoxyacetic acid, there was obtained theabove-mentioned desired compound.

¹H-NMR (CDCl₃) δ: 2.78 (t, J=6 Hz, 2H), 3.33 (s, 3H), 3.61 (s, 2H), 3.66(t, J=6 Hz, 2H), 5.27 (s, 2H), 7.54 (d, J=8 Hz, 2H), 8.23 (d, J=8 Hz,2H).

Reference Example 7

[Synthesis of 4-nitrobenzyl 6-methoxy-3-oxohexanate]

Reactions were carried out similar to those of used in Reference Example1, except that the same molar quantity of 4-methoxybutyric acid was usedin place of ethoxyacetic acid, there was obtained the above-mentioneddesired compound.

¹H-NMR (CDCl₃) δ: 1.83-1.93 (m, 2H), 2.64 (t, J=7 Hz, 2H), 3.29 (s, 3H),3.34-3.41 (m, 2H), 3.59 (s, 2H), 5.28 (s, 2H), 7.54 (d, J=8 Hz, 2H),8.22 (d, J=8 Hz, 2H)

Reference Example 8

[Synthesis of 4-nitrobenzyl 4,4-dimethoxyacetoacetate]

Reactions were carried out similar to those of used in Reference Example1, except that the same molar quantity of dimethoxyacetic acid was usedin place of ethoxyacetic acid, there was obtained the above-mentioneddesired compound.

¹H-NMR (CDCl₃) δ: 3.42 (s, 6H), 3.69 (s, 2H), 4.55 (s, 1H), 5.28 (s,2H), 7.54 (d, J=9 Hz, 2H), 8.23 (d, J=9 Hz, 2H).

Reference Example 9

[Synthesis of 4-nitrobenzyl 4,4-diethoxyacetoacetate]

Reactions were carried out similar to those of used in Reference Example1, except that the same molar quantity of diethoxyacetic acid was usedin place of ethoxyacetic acid, there was obtained the above-mentioneddesired compound.

¹H-NMR (CDCl₃) δ: 1.23 (t, J=7 Hz, 6H), 3.5-3.8 (m, 6H), 4.65, (s, 1H),5.28 (s, 2H), 7.54 (d, J=8.9 Hz, 2H), 8.23 (d, J=8 Hz, 2H).

Reference Example 10

[Synthesis of 4-nitrobenzyl 5,5-dimethoxy-3-oxopentanate]

Reactions were carried out similar to those of used in Reference Example1, except that the same molar quantity of 3,3-dimethoxypropionic acidwas used in place of ethoxyacetic acid, there was obtained theabove-mentioned desired compound.

¹H-NMR (CDCl₃) δ: 2.85 (d, J=5.3 Hz, 2H), 3.36 (s, 6H), 3.62 (s, 2H),4.76 (t, J=5.3 Hz, 1H), 5.28 (s, 2H), 7.54 (d, J=8.6 Hz, 2H), 8.23 (d,J=8.6 Hz, 2H).

Reference Example 11

[Synthesis of 4-nitrobenzyl 5,5-ethylenedioxy-3-oxohexanate]

Reactions were carried out similar to those of used in Reference Example1, except that the same molar quantity of 3,3-ethylenedioxybutyric acidwas used in place of ethoxyacetic acid, there was obtained theabove-mentioned desired compound.

¹H-NMR (CDCl₃) δ: 1.40 (s, 3H), 2.89 (s, 2H), 3.69 (s, 2H), 3.94-4.00(m, 4H), 5.27 (s, 2H), 7.54 (d, J=8.3 Hz, 2H), 8.23 (d, J=8.6 Hz, 2H).

Reference Example 12

[Synthesis of 4-nitrobenzyl 6,6-ethylenedioxy-3-oxoheptanate]

Reactions were carried out similar to those of used in Reference Example1, except that the same molar quantity of 4,4-ethylenedioxyvaleric acidwas used in place of ethoxyacetic acid, there was obtained theabove-mentioned desired compound.

¹H-NMR (CDCl₃) δ: 1.31 (s, 3H), 2.02 (t, J=7.3 Hz, 2H), 2.61 (t, J=7.3Hz, 2H), 3.58 (s, 2H), 3.85-3.97 (m, 4H), 5.27 (s, 2H), 7.54 (d, J=8.6Hz, 2H), 8.23 (d, J=8.6 Hz, 2H).

Reference Example 13

[Synthesis of 4-nitrobenzyl 4-methylthioacetoacetate]

Reactions were carried out similar to those of used in Reference Example1, except that the same molar quantity of methylthioacetic acid was usedin place of ethoxyacetic acid, there was obtained the above-mentioneddesired compound.

¹H-NMR (CDCl₃) δ: 2.06(s, 3H), 3.30 (s, 2H) 3.79 (s, 2H), 5.28 (s, 2H),7.54 (d, J=8.6 Hz, 2H), 8.23 (d, J=8.6 Hz, 2H).

Reference Example 14

[Synthesis of 4-nitrobenzyl 4-ethylthioacetoacetate]

Reactions were carried out similar to those of used in Reference Example1, except that the same molar quantity of ethylthioacetic acid was usedin place of ethoxyacetic acid, there was obtained the above-mentioneddesired compound.

¹H-NMR (CDCl₃) δ: 1.23 (t, J=7.3 Hz, 3H), 2.49 (q, J=7.3 Hz, 2H), 3.34(s, 2H), 3.80 (s, 2H), 5.28 (s, 2H), 7.54 (d, J=9 Hz, 2H), 8.23 (d, J=9Hz, 2H).

Reference Example 15

[Synthesis of 4-nitrobenzyl 5-methylthio-3-oxopentanate]

Reactions were carried out similar to those of used in Reference Example1, except that the same molar quantity of 3-methylthiopropionic acid wasused in place of ethoxyacetic acid, there was obtained theabove-mentioned desired compound.

¹H-NMR (CDCl₃) δ: 2.11 (s, 3H), 2.72-2.90 (m, 4H), 3.59 (s, 2H), 5.28(s, 2H), 7.54 (d, J=8.2 Hz, 2H), 8.23 (d, J=8.6 Hz, 2H).

Reference Example 16

[Synthesis of 4-nitrobenzyl 3-oxo-5-(2-pyridylthio)pentanate]

Reactions were carried out similar to those of used in Reference Example1, except that the same molar quantity of 3-(2-pyridylthio)propionicacid was used in place of ethoxyacetic acid, there was obtained theabove-mentioned desired compound.

¹H-NMR (CDCl₃) δ: 3.04 (t, J=7 Hz, 2H), 3.39 (t, J=7 Hz, 2H), 3.58 (s,2H), 5.26 (s, 2H), 6.98 (dd, J=5.0 Hz, 7.3 Hz, 1H), 7.14 (d, J=7.6 Hz,1H), 7.44-7.54 (m, 3H), 8.21 (d, J=8.6 Hz, 2H), 8.39 (d, J=5.0 Hz, 1H).

Reference Example 17

[Synthesis of 4-nitrobenzyl 6-ethylthio-3-oxohexanate]

Reactions were carried out similar to those of used in Reference Example1, except that the same molar quantity of 4-ethylthiobutyric acid wasused in place of ethoxyacetic acid, there was obtained theabove-mentioned desired compound.

¹H-NMR (CDCl₃) δ: 1.24 (t, J=7.3 Hz, 3H), 1.85-1.95 (m, 2H), 2.46-2.57(m, 4H), 2.69 (t, J=7 Hz, 2H), 3.57 (s, 2H), 5.27 (s, 2H), 7.54 (d,J=8.2 Hz, 2H), 8.24 (d, J=8.6 Hz, 2H).

Reference Example 18

[Synthesis of ethyl 4-cyclopentyloxyacetoacetate]

Under nitrogen gas stream, into a suspension of 1,2-dimethoxyethane (20ml) containing sodium hydride (1.3 g) was added cyclopentylalcohol (2.36ml) under an ice-cooling condition and the mixture was stirred at roomtemperature. 15 Minutes after the stirring, ethyl 4-chloroacetoacetate(3.29 g) was added thereto under an ice-cooling condition and stirred atroom temperature for 18 hours. Next, under an ice-cooling condition, thereaction mixture was neutralized with 10% hydrochloric acid, thenextracted with diethyl ether. The organic layer was washed with anaqueous solution saturated with sodium chloride, an aqueous solutionsaturated with sodium hydrogencarbonate, and an aqueous solutionsaturated with sodium chloride in this order, then the washed organiclayer was dried with anhydrous sodium sulfate, and the solvent wasremoved by distillation. The residue was purified by subjecting a silicagel column chromatography (silica gel: manufactured by Merck & Co.,eluate:diethyl ether:n-hexane=1:4). there was obtained theabove-mentioned desired compound (2.55 g).

¹H-NMR (CDCl₃) δ: 1.28 (t, J=7 Hz, 3H), 1.53-1.71 (m, 8H), 3.52 (s, 2H),3.92-3.98 (m, 1H) 4.04 (s, 2H), 4.19 (q, J=7 Hz, 2H).

Reference Example 19

[Synthesis of ethyl 4-(3,7-dimethyloctyloxy)acetoacetate]

Reactions were carried out similar to those of used in Reference Example18, except that the same molar quantity of 3,7-dimethyloctanol was usedin place of cyclopentyl alcohol, there was obtained the above-mentioneddesired compound.

¹H-NMR (CDCl₃) δ: 0.85-0.90 (m, 9H), 1,10-1.68 (m, 13H), 3.44-3.54 (m,2H), 3.53 (s, 2H), 4.09 (s, 2H), 4.16-4.25 (m, 2H).

Reference Example 20

[Synthesis of ethyl 4-(tetrahydropyran-4-yloxy)acetoacetate]

Reactions were carried out similar to those of used in Reference Example18, except that the same molar quantity of tetrahydropyran-4-ol was usedin place of cyclopentyl alcohol, there was obtained the above-mentioneddesired compound.

¹H-NMR (CDCl₃) δ: 1.29 (t, J=7.3 Hz, 3H), 1,56-1.69 (m, 2H), 1.89-1.93(m, 2H), 3.41-3.50 (m, 3H), 3.55 (s, 2H), 3.90-3.98 (m, 2H), 4.15 (s,2H), 4.20 (q, J=7.3 Hz, 2H).

Reference Example 21

[Synthesis of ethyl 4-(2-t-butoxyethoxy)acetoacetate]

Reactions were carried out similar to those of used in Reference Example18, except that the same molar quantity of ethylene glycol mono-t-butylether was used in place of cyclopentyl alcohol, there was obtained theabove-mentioned desired compound.

¹H-NMR (CDCl₃) δ: 1.20 (s, 9H), 1.28 (t, J=7 Hz, 3H), 3.52-3.56 (m, 2H),3.57 (s, 2H), 3.62-3.66 (m, 2H), 4.20 (s, 2H), 4.20 (q, J=7 Hz, 2H).

Reference Example 22

[Synthesis of ethyl 4-(3-methoxypropoxy)acetoacetate]

Reactions were carried out similar to those of used in Reference Example18, except that the same molar quantity of 3-methoxypropanol was used inplace of cyclopentyl alcohol, there was obtained the above-mentioneddesired compound.

¹H-NMR (CDCl₃) δ: 1.28 (t, J=7 Hz, 3H), 1.83-1.92 (m, 2H), 3.34 (s, 3H),3.47 (t, J=6 Hz, 2H), 3.53 (s, 2H),3.58 (t, J=6 Hz, 2H), 4.11 (s, 2H),4.20 (q, J=7 Hz, 2H).

Reference Example 23

[Synthesis of ethyl 4-(3-ethoxypropoxy)acetoacetate]

Reactions were carried out similar to those of used in Reference Example18, except that the same molar quantity of 3-ethoxypropanol was used inplace of cyclopentyl alcohol, there was obtained the above-mentioneddesired compound.

¹H-NMR (CDCl₃) δ: 1.20 (t, J=7 Hz, 3H), 1.28 (t, J=7 Hz, 3H), 1.83-1.92(m, 2H), 3.44-3.52 (m, 4H), 3.53 (s, 2H), 3.59 (t, J=6.3 Hz, 2H), 4.11(s, 2H), 4.20 (q, J=7 Hz, 2H).

Reference Example 24

[Synthesis of ethyl 4-(2-pyridylthio)acetoacetate]

Reactions were carried out similar to those of used in Reference Example18, except that the same molar quantity of 2-mercaptopyridine was usedin place of cyclopentyl alcohol, there was obtained the above-mentioneddesired compound.

¹H-NMR (CDCl₃) δ: 1.28 (t, J=7 Hz, 3H), 3.70 (s, 2H), 4.05 (s, 2H), 4.20(q, J=7 Hz, 2H), 7.00 (dd, J=4.96 Hz, 7.26 Hz, 1H), 7.23 (d, J=7.9 Hz,1H), 7.50 (m, 1H), 8.36 (d, J=4.3 Hz, 1H).

Reference Example 25

[Synthesis of ethyl 4-(3-methylphenoxy)acetoacetate]

Reactions were carried out similar to those of used in Reference Example18, except that the same molar quantity of m-cresol was used in place ofcyclopentyl alcohol, there was obtained the above-mentioned desiredcompound.

¹H-NMR (CDCl₃) δ: 1.26 (t, J=7 Hz, 3H), 2.33 (s, 3H), 3.63 (s, 2H), 4.19(q, J=7 Hz, 2H), 4.62 (s, 2H), 5.39-6.74 (m, 2H), 6.82 (d, J=8 Hz, 1H),7.18 (t, J=8 Hz, 1H).

Reference Example 26

[Synthesis of ethyl 4-(3-trifluoromethylphenoxy)acetoacetate]

Reactions were carried out similar to those of used in Reference Example18, except that the same molar quantity of 3-trifluoromethylphenol wasused in place of cyclopentyl alcohol, there was obtained theabove-mentioned desired compound.

¹H-NMR (CDCl₃) δ: 1.26 (t, J=7 Hz, 3H), 3.64 (s, 2H), 4.20 (q, J=7 Hz,2H), 4.72 (s, 2H), 7.06-7.14 (m, 2H), 7.26-7.29 (m, 1H), 7.43 (t, J=8Hz, 1H).

Reference Example 27

[Synthesis of ethyl 4-(3-methoxyphenoxy)acetoacetate]

Reactions were carried out similar to those of used in Reference Example18, except that the same molar quantity of 3-methoxyphenol was used inplace of cyclopentyl alcohol, there was obtained the above-mentioneddesired compound.

¹H-NMR (CDCl₃) δ: 1.30 (m, 3H), 3.63 (s, 2H), 3.79 (s, 3H), 4.20 (m,2H), 4.63 (s, 2H), 6.40-6.60 (m 3H), 7.10-7.30 (m, 1H).

Reference Example 28

[Synthesis of ethyl 4-(4-carboxyphenoxy)acetoacetate]

Under nitrogen gas stream, into a suspension of dimethylformamide (5 ml)containing sodium hydride (0.72 g) was added a solution ofdimethylformamide (5 ml) containing 4-hydroxybenzoic acid (0.69 g) underan ice-cooling condition and the mixture was stirred at roomtemperature. One hour after the stirring, ethyl 4-chloroacetoacetate(0.82 g) was added thereto under an ice-cooling condition and stirred atroom temperature for 18 hours. Next, under an ice-cooling condition, thereaction mixture was acidified with 10% hydrochloric acid, thenextracted with ethyl acetate. The organic layer was washed with anaqueous solution saturated with sodium chloride, then the washed organiclayer was dried with anhydrous sodium sulfate, and the solvent wasremoved by distillation. The residue was purified by subjecting a silicagel column chromatography (silica gel: manufactured by Merck & Co.,eluant:chloroform:methanol:acetic acid=98:2:1), there was obtained theabove-mentioned desired compound (0.32 g).

¹H-NMR (CDCl₃) δ: 1.96 (t, J=7 Hz, 3H), 3.72 (s, 2H), 4.12 (q, J=7 Hz,2H), 5.02 (s, 2H), 6.99 (d, J=8.3 Hz, 2H), 7.87 (d, J=8.3 Hz, 2H), 12.7(brs, 1H).

Example 1

[Synthesis of4,7-dihydro-5-methoxymethyl-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine]

A mixture of 3-amino-4-(4-phenylthiophenyl)pyrazole (0.27 g) which wasprepared in accordance with the method disclosed in WO 92/06096, methyl4-methoxyacetoacetate (0.14 ml) and acetic acid (0.5 ml) was heated at100 to 110° C. and stirred. After 3 hours, ethyl alcohol was added tothe reaction mixture and concentrated under a reduced pressure. To theresidue thus obtained was added ethyl acetate and stirred under anice-cooled condition. The deposited solid matters were as collected byfiltration, and washed with ethyl acetate and then dried, there wasobtained the above-mentioned desired compound (0.28 g).

Melting point: 163-165° C.; ¹H-NMR (CDCl₃) δ: 3.52 (s, 3H), 4.53 (s,2H), 5.77 (s, 1H), 7.28-7.39 (m, 9H), 7.95 (s, 1H), 9.66 (brs, 1H).

Example 2

[Synthesis of4,7-dihydro-5-ethoxymethyl-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine]

Reactions were carried out similar to those of used in Example 1, exceptthat the same molar quantity of 4-nitrobenzyl 4-ethoxyacetoacetate,obtained in Reference Example 1, was used in place of methyl4-methoxyacetoacetate, there was obtained the above-mentioned desirescompound.

Melting point: 169-171° C.; ¹H-NMR (DMSO-d₆) δ: 1.18 (t, J=7 Hz, 3H),3.56 (q, J=7 Hz, 2H), 4.46 (s, 2H), 5.82 (s, 1H), 7.32-7.42 (m, 7H),7.57 (d, J=7.92 Hz, 2H), 8.17 (s, 1H), 12.0 (s, 1H).

Example 3

[Synthesis of5-cyclopentyloxymethyl-4,7-dihydro-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1,5-a]-pyrimidine]

Reactions were carried out similar to those of used in Example 1, exceptthat the same molar quantity of methyl 4-cyclopentyloxyacetoacetate,obtained in Reference Example 18, was used in place of methyl4-methoxyacetoacetate, there was obtained the above-mentioned desirescompound.

Melting point: 207-210° C.; ¹H-NMR (CDCl₃) δ: 1.58-1.81 (m, 8H),4.09-4.13 (m, 1H), 4.53 (s, 2H), 5.75 (s, 1H), 7.26-7.39 (m, 9H), 7.99(s, 1H), 9.43 (brs, 1H).

Example 4

[Synthesis of5-cyclohexyloxymethyl-4,7-dihydro-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1,5-a]-pyrimidine]

Reactions were carried out similar to those of used in Example 1, exceptthat the same molar quantity of ethyl 4-cyclohexyloxyacetoacetate wasused in place of methyl 4-methoxyacetoacetate, there was obtained theabove-mentioned desired compound.

Melting point: 220-224° C.; ¹H-NMR (CDCl₃) δ: 1.23-1.94 (m, 10H),3.45-3.52 (m, 1H), 4.60 (s, 2H), 5.76 (s, 1H), 7.25-7.41 (m, 9H), 7.99(s, 1H), 9.58 (brs, 1H).

Example 5

[Synthesis of4,7-dihydro-5-isopropoxymethyl-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine]

A mixture of 3-amino-4-(4-phenylthiophenyl)pyrazole (0.3 g), ethyl4-isopropoxyacetoacetate (0.4 g) and acetic acid (0.5 ml) was heated at100 to 110° C. and stirred. 3 Hours after, the reaction mixture wasdiluted with ethyl acetate and the organic layer was washed with waterand an aqueous solution saturated with sodium chloride in this order,then dried with anhydrous sodium sulfate. After removal of the solventby distillation, the residue thus obtained was purified by a silica gelcolumn chromatography (silica gel was the same as defined above;eluant:ethyl acetate:n-hexane=3:1), there was obtained theabove-mentioned desired compound (0.25 g).

Melting point: 146-151° C.; ¹H-NMR (CDCl₃) δ: 1.27 (d, J=6.3 Hz, 6H),3.76-3.85 (m, 1H), 4.55 (s, 2H), 5.75 (s, 1H), 7.29-7.44 (m, 9H), 8.04(s, 1H), 9.23 (brs, 1H).

Example 6

[Synthesis of5-t-butoxymethyl-4,7-dihydro-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine]

Reactions were carried out similar to those of used in Example 5, exceptthat the same molar quantity of 4-nitrobenzyl 4-t-butoxyacetoacetate,obtained in Reference Example 2, was used in place of ethyl4-isopropoxyacetoacetate, there was obtained the above-mentioned desiredcompound.

Melting point: 113-116° C.; ¹H-NMR (CDCl₃) δ: 1.29 (s, 9H), 4.52 (s,2H), 5.80 (s, 1H), 7.28-7.36 (m, 9H), 7.98 (s, 1H).

Example 7

[Synthesis of5-benzyloxymethyl-4,7-dihydro-7-oxo-3-(4-phenylthiophenyl)pyrazolo-[1,5-a]pyrimidine]

Reactions were carried out similar to those of used in Example 1, exceptthat the same molar quantity of ethyl 4-benzyloxyacetoacetate was usedin place of methyl 4-methoxyacetoacetate, there was obtained theabove-mentioned desired compound.

Melting point: 183-186° C.; ¹H-NMR (DMSO-d₆) δ: 4.53 (s, 2H), 4.63 (s,2H), 5.88 (s, 1H), 7.30-7.43 (m, 12H), 7.56 (d, J=8.25 Hz, 2H), 8.16 (s,1H), 12.0 (s, 1H).

Example 8

[Synthesis of4,7-dihydro-5-(3,7-dimethyloctyloxymethyl)-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine]

Reactions were carried out similar to those of used in Example 5, exceptthat the same molar quantity of ethyl4-(3,7-dimethyloctyloxy)acetoacetate, obtained in Reference Example 19,was used in place of ethyl 4-isopropoxyacetoacetate, there was obtainedthe above-mentioned desired compound.

¹H-NMR (CDCl₃) δ: 0.86 (t, J=6.6 Hz, 9H), 1.10-1.63 (m, 10H), 3.63 (t,J=6.6 Hz, 2H), 4.52 (s, 2H), 5.78 (s, 1H), 7.28-7.40 (m, 9H), 8.03 (s,1H).

Example 9

[Synthesis of5-acetoxymethyl-4,7-dihydro-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine]

Reactions were carried out similar to those if used in Example 1, exceptthat the same molar quantity of ethyl 4-acetoxyacetoacetate was used inplace of ethyl 4-methoxyacetoacetate, there was obtained theabove-mentioned desired compound.

Melting point: 118-130° C.; ¹H-NMR (DMSO-d₆) δ: 2.14 (s, 3H), 5.06 (s,2H), 5.89 (s, 1H), 7.31-7.42 (m, 7H), 8.10 (br, 2H), 8.36 (brs, 1H),12.1 (brs, 1H).

Example 10

[Synthesis of4,7-dihydro-5-hydroxymethyl-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1.5-a]pyrimidine]

Into a methanol suspension (15 ml) containing5-acetoxymethyl-4,7-dihydro-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1.5-a]pyrimidine(0.4 g), obtained in Example 9, was added an aqueous solution of2N-sodium hydroxide (5 ml), and the mixture was stirred at roomtemperature. 4 Hours after, under an ice-cooling condition, pH of thereaction mixture was adjusted to pH 1-3 by adding 10% hydrochloric acid,then water was added and stirred for 1 hour. Then the deposit wascollected by filtration. Next, the deposit was washed with water, anddried, then purified by means of a silica gel column chromatography(silica gel was the same as defined above;eluant:chloroform:methanol=98:2), there was obtained the above-mentioneddesired compound (0.25 g).

Melting point: 200-203° C.; ¹H-NMR (DMSO-d₆) δ: 4.48 (d, J=5.6 Hz, 2H),5.70 (t, J=5.9 Hz, 1H), 5.85 (s, 1H), 7.30-7.42 (m, 7H), 7.59 (d, J=8.25Hz, 2H), 8.16 (s, 1H), 11.8 (brs, 1H).

Example 11

[Synthesis of4,7-dihydro-7-oxo-3-(4-phenylthiphenyl)-5-(tetrahydopyran-4-yloxymethyl)pyrazolo[1,5-a]pyrimidine]

Reactions were carried out similar to those of used in Example 1, exceptthat the same molar quantity of ethyl4-(tetrahydropyran-4-yloxy)acetoacetate, obtained in Reference Example20, was used in place of methyl 4-methoxyacetoacetate, there wasobtained the above-mentioned desired compound.

Melting point: 213-218° C.; ¹H-NMR (DMSO-d₆) δ: 1.41-1.55 (m, 2H),1.88-1.92 (m, 2H), 3.31-3.38 (m, 2H), 3.62-3.69 (m, 1H), 3.79-3.86 (m,2H), 4.53 (s, 2H), 5.86 (s, 1H), 7.30-7.43 (m, 7H), 7.57 (d, J=7.9 Hz,2H), 8.17 (s, 1H), 11.96 (s, 1H).

Example 12

[Synthesis of4,7-dihydro-7-oxo-5-phenoxymethyl-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine]

Reactions were carried out similar to those of used in Example 1, exceptthat the same molar quantity of ethyl 4-phenoxyacetoacetate was used inplace of methyl 4-methoxy-acetoacetate, there was obtained theabove-mentioned desired compound.

Melting point: 176-178° C.; ¹H-NMR (DMSO-d₆) δ: 5.12 (s, 2H), 5.92 (s,1H), 6.98-7.06 (m, 3H), 7.31-7.44 (m, 9H), 7.61 (d, J=8.25 Hz, 2H), 8.20(s, 1H), 12.2 (s, 1H).

Example 13

[Synthesis of4,7-dihydro-7-oxo-3-(4-phenylthiophenyl)-5-(3-pyridyloxymethyl)pyrazolo[1,5-a]pyrimidine]

Reactions were carried out similar to those of used in Example 1, exceptthat the same molar quantity of ethyl 4-(3-pyridyloxy)acetoacetate wasused in place of methyl 4-methoxyacetoacetate, there was obtained theabove-mentioned desired compound.

Melting point: 214-220° C. (decomposed); ¹H-NMR (DMSO-d₆) δ: 5.19 (s,2H), 5.95 (s, 1H), 7.3-7.6 (m, 9H), 7.62 (d, J=8.25 Hz, 2H), 8.21-8.25(m, 2H), 8.42 (d, J=2.97 Hz, 1H), 12.2 (brs, 1H).

Example 14

[Synthesis of4,7-dihydro-5-(2-methoxyethoxymethyl)-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine]

Reactions were carried out similar to those of used in Example 1, exceptthat the same molar quantity of ethyl 4-(2-methoxyethoxy)acetoacetatewas used in place of methyl 4-methoxyacetoacetate, there was obtainedthe above-mentioned desired compound.

Melting point: 142-144° C.; ¹H-NMR (DMSO-d₆) δ: 3.26 (s, 3H), 3.49-3.53(m, 2H), 3.67 (m, 2H), 4.51 (s, 2H), 5.85 (s, 1H), 7.32-7.42 (m, 7H),7.58 (d, J=8.3 Hz, 2H), 8.17 (s, 1H), 11.94 (s, 1H).

Example 15

[Synthesis of5-(2-t-butoxyethoxymethyl)-4,7-dihydro-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine]

Reactions were carried out similar to those of used in Example 1, exceptthat the same molar quantity of ethyl 4-(2-t-butoxyethoxy)acetoacetate,which was obtained in Reference Example 21, was used in place of methyl4-methoxyacetoacetate, there was obtained the above-mentioned desiredcompound.

Melting point: 167-168° C.; ¹H-NMR (DMSO-d₆) δ: 1.13 (s, 9H), 3.47-3.50(m, 2H), 3.58-3.62 (m, 2H), 4.51 (s, 2H), 5.90 (s, 1H), 7.32-7.42 (m,7H), 7.57 (d, J=8.3 Hz, 2H), 8.16 (s, 1H), 11.93 (s, 1H).

Example 16

[Synthesis of4,7-dihydro-5-(2-hydroxyethoxymethyl)-7-oxo-3-(4-phenylthiophenyl)pyrazolo-[1,5-a]pyrimidine]

5-(2-t-Butoxyethoxymethyl-4,7-dihydro-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine(450 mg), which was obtained in Example 15, was dissolved intrifluoroacetic acid (4 ml) and this solution was stirred at roomtemperature. After 26 hours, this solution was neutralized with anaqueous solution of 2N-sodium hydroxide. The formed precipitates werecollected by filtration, and washed with water and dried, these wasobtain the above-mentioned desired compound (380 mg).

Melting point: 189-194° C.; ¹H-NMR (DMSO-d₆) δ: 3.57 (s, 4H), 4.52 (s,2H), 4.78 (brs, 1H), 5.90 (s, 1H), 7.30-7.43 (m, 7H), 7.58 (d, J=8.3 Hz,2H), 8.17 (s, 1H), 11.92 (s, 1H).

Example 17

[Synthesis of4,7-dihydro-5-(3-methoxypropoxymethyl)-7-oxo-3-(4-phenylthiophenyl)pyrazolo-[1,5-a]pyrimidine]

Reactions were carried out similar to those of used in Example 5, exceptthat the same molar quantity of ethyl 4-(3-methoxypropoxy)acetoacetate,which was obtained in Reference Example 22, was used in place of ethyl4-isopropoxyacetoacetate, there was obtained the above-mentioned desiredcompound.

Melting point: 156-158° C.; ¹H-NMR (CDCl₃) δ: 1.86-1.95 (m, 2H), 3.18(s, 3H), 3.48 (t, J=6 Hz, 2H), 3.70 (t, J=6 Hz, 2H), 4.59 (s, 2H), 5.78(s, 1H), 7.23-7.34 (m, 9H), 7.91 (s, 1H), 10.21 (brs, 1H).

Example 18

[Synthesis of4,7-dihydro-5-(3-ethoxypropoxymethyl)-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine]

Reactions were carried out similar to those of used in Example 5, exceptthat the same molar quantity of ethyl 4-(3-ethoxypropoxy)acetoacetate,which was obtained in Reference Example 23, was used in place of ethyl4-isopropoxyacetoacetate, there was obtained the above-mentioned desiredcompound.

Melting point: 132-134° C.; ¹H-NMR (CDCl₃) δ: 1.11 (t, J=7 Hz, 3H),1.87-1.96 (m, 2H), 3.39 (q, J=7 Hz, 2H), 3.52 (t, J=6 Hz, 2H), 3.71 (t,J=6 Hz, 2H), 4.61 (s, 2H), 5.80 (s, 1H), 7.20-7.32 (m, 9H), 7.86 (s,1H), 10.36 (brs, 1H).

Example 19

[Synthesis of4,7-dihydro-7-oxo-3-(4-phenylthiophenyl)-5-(tetrahydrofuran-2-yl)pyrazolo[1,5-a]pyrimidine]

Reactions were carried out similar to those of used in Example 5, exceptthat the same molar quantity of 4-nitrobenzylβ-oxo-tetrahydro-2-franpropionate, which was obtained in ReferenceExample 3, was used in place of ethyl 4-isopropoxyacetoacetate, therewas obtained the above-mentioned desired compound.

Melting point: 104-108° C.; ¹H-NMR (CDCl₃) δ: 1.98-2.13 (m, 3H),2.45-2.54 (m, 1H), 3.97-4.14 (m, 2H), 4.93-4.98 (m, 1H), 5.73 (s, 1H),7.30-7.43 (m, 9H), 8.02 (s, 1H), 9.29 (brs, 1H).

Example 20

[Synthesis of4,7-dihydro-7-oxo-3-(4-phenylthiophenyl)-5-(tetrahydropyran-2-yl)pyrazolo[1,5-a]pyrimidine]

Reactions were carried out similar to those of used in Example 1, exceptthat the same molar quantity of 4-nitrobenzylβ-oxo-tetrahydro-2-pyranpropionate, which was obtained in ReferenceExample 4, was used in place of methyl 4-methoxyacetoacetate, there wasobtained the above-mentioned desired compound.

Melting point: 209-211° C.; ¹H-NMR (DMSO-d₆) δ: 1.44-1.56 (m, 4H),1.87-1.99 (m, 2H), 3.36-3.52 (m, 1H), 4.02-4.08 (m, 1H), 4.41 (d, J=10Hz, 1H), 5.76 (s, 1H), 7.33-7.43 (m, 7H), 7.55 (d, J=7.9 Hz, 2H), 8.14(s, 1H), 11.81 (s, 1H).

Example 21

[Synthesis of4,7-dihydro-5-(2-ethoxyethyl)-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine]

Reactions were carried out similar to those of used in Example 5, exceptthat the same molar quantity of 4-nitrobenzyl 5-ethoxy-3-oxopentanate,which was obtained in Reference Example 5, was used in place of ethyl4-isopropoxyacetoacetate, there was obtained the above-mentioned desiredcompound.

Melting point: 142-143° C.; ¹H-NMR (CDCl₃) δ: 1.63 (t, J=7 Hz, 3H), 2.92(t, J=5.3 Hz, 2H), 3.58 (q, J=7 Hz, 2H), 3.83 (t, J=5.3 Hz, 2H), 5.71(s, 1H), 7.26-7.41 (m, 9H), 8.02 (s, 1H), 10.33 (brs, 1H).

Example 22

[Synthesis of4,7-dihydro-5-(2-methoxyethyl)-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine]

Reactions were carried out similar to those of used in Example 5, exceptthat the same molar quantity of 4-nitrobenzyl 5-methoxy-3-oxopentanate,which was obtained in Reference Example 6, was used in place of ethyl4-isopropoxyacetoacetate, there was obtained the above-mentioned desiredcompound.

Melting point: 178-181° C.; ¹H-NMR (CDCl₃) δ: 2.93 (t, J=5.3 Hz, 2H),3.47 (s, 3H), 3.83 (t, J=5.3 Hz, 2H), 5.70 (s, 1H), 7.26-7.42 (m, 9H),8.02 (s, 1H), 10.43 (brs, 1H).

Example 23

[Synthesis of4,7-dihydro-5-(3-methoxypropyl)-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine]

Reactions were carried out similar to those of used in Example 5, exceptthat the same molar quantity of 4-nitrobenzyl 6-methoxy-3-oxohexanate,which was obtained in Reference Example 7, was used in place of ethyl4-isopropoxyacetoacetate, there was obtained the above-mentioned desiredcompound.

Melting point: 183-184° C.; ¹H-NMR (CDCl₃) δ: 1.99-2.08 (m, 2H), 2.85(t, J=6.3 Hz, 2H), 3.28 (s, 3H), 3.52 (t, J=5.6 Hz, 2H), 5.66 (s, 1H),7.23-7.36 (m, 9H), 7.88 (s, 1H), 11.24 (brs, 1H).

Example 24

[Synthesis of4,7-dihydro-5-dimethoxymethyl-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine]

A mixture of 3-amino-4-(4-phenylthiophenyl)pyrazole (0.53 g),4-nitrobenzyl 4,4-dimethoxyacetoacetate (0.71 g), which was obtained inReference example 8, and acetic acid (4 ml) was stirred at roomtemperature. After 24 hours, this solution was neutralized with anaqueous solution saturated with sodium hydrogencarbonate, and extractedwith ethyl acetate. The organic layer was washed with an aqueoussolution saturated with sodium chloride, and dried with anhydrous sodiumsulfate and the solvent was removed by distillation. The residue thusobtained was subjected to a silica gel column chromatography (silicagel: the same as defined above, eluate:ethyl acetate:n-hexane=7:3) toseparate and purified, there was obtained the above-mentioned desiredcompound (0.39 g).

Melting point: 157-163° C.; ¹H-NMR (DMSO-d₆) δ: 3.44 (s, 6H), 5.40 (s,1H), 6.00 (s, 1H), 7.30-7.44 (m, 9H), 8.01 (s, 1H), 9.04 (brs, 1H).

Example 25

[Synthesis of5-diethoxymethyl-4,7-dihydro-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine]

Reactions were carried out similar to those of used in Example 24,except that the same molar quantity of 4-nitrobenzyl4,4-diethoxyacetoacetate, which was obtained in Reference Example 9, wasused in place of 4-nitrobenzyl 4,4-dimethoxyacetoacetate, there wasobtained the above-mentioned desired compound.

Melting point: 170-183° C. (decomposed); ¹H-NMR (CDCl₃) δ: 1.19 (t,J=6.93 Hz, 6H), 3.56-3.68 (m, 4H), 5.50 (s, 1H), 5.88 (s, 1H), 7.31-7.44(m, 7H), 7.56 (d, J=8.25 Hz, 2H), 8.18 (s, 1H), 12.1 (brs, 1H).

Example 26

[Synthesis of4,7-dihydro-5-(2,2-dimethoxyethyl)-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1,5-a]-pyrimidine]

Reactions were carried out similar to those of used in Example 24,except that the same molar quantity of 4-nitrobenzyl5,5-dimethoxy-3-oxopentanate, which was obtained in Reference Example10, was used in place of 4-nitrobenzyl 4,4-dimethoxyacetoacetate, therewas obtained the above-mentioned desired compound.

Melting point: 175-178° C.; ¹H-NMR (CDCl₃) δ: 2.99 (d, J=4.62 Hz, 2H),3.47 (s, 6H), 4.74 (t, J=4.62 Hz, 1H), 5.72 (s, 1H), 7.28-7.40 (m, 9H),7.99 (s, 1H), 10.2 (brs, 1H).

Example 27

[Synthesis of4,7-dihydro-5-(2,2-ethylenedioxypropyl)-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine]

Reactions were carried out similar to those of use in Example 1, exceptthat the same molar quantity of 4-nitrobenzyl5,5-ethylenedioxy-3-oxohexanate, which was obtained in Reference Example11, was used in place of methyl 4-methoxyacetoacetate, there wasobtained the above-mentioned desired compound.

Melting point: 199-202° C.; ¹H-NMR (DMSO-d₆) δ: 1.34 (s, 3H), 3.01 (s,2H), 3.89 (s, 4H), 5.72 (s, 1H), 7.33-7.44 (m, 7H), 7.56 (d, J=7.9 Hz,2H), 8.16 (s, 1H), 11.7 (brs, 1H).

Example 28

[Synthesis of4,7-dihydro-5-(3,3-ethylenedioxybutyl)-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine]

Reactions were carried out similar to those of used in Example 1, exceptthat the same molar quantity of 4-nitrobenzyl6,6-ethylenedioxy-3-oxoheptanate, which was obtained in ReferenceExample 12, was used in place of methyl 4-methoxyacetoacetate, there wasobtained the above-mentioned desired compound.

Melting point: 192-196° C.; ¹H-NMR (DMSO-d₆) δ: 1.29 (s, 3H), 1.96-2.02(m, 2H), 2.66-2.73 (m, 2H), 3.90 (s, 4H), 5.69 (s, 1H), 7.33-7.43 (m,7H), 7.58 (d, J=8.25 Hz, 2H), 8.12 (s, 1H), 11.8 (brs, 1H).

Example 29

[Synthesis of4,7-dihydro-5-methylthiomethyl-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine]

Reactions were carried out similar to those of used in Example 1, exceptthat the same molar quantity of 4-nitrobenzyl 4-methylthioacetoacetate,which was obtained in Reference Example 13, was used in place of methyl4-methoxyacetoacetate, there was obtained the above-mentioned desiredcompound.

Melting point: 221-224° C.; ¹H-NMR (DMSO-d₆) δ: 2.10 (s, 3H), 3.70 (s,2H), 5.82 (s, 1H), 7.33-7.44 (m, 7H), 7.57 (d, J=8.25 Hz, 2H), 8.17 (s,1H), 11.9 (brs, 1H).

Example 30

[Synthesis of4,7-dihydro-5-ethylthiomethyl-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine]

Reactions were carried out similar to those of used in Example 1, exceptthat the same molar quantity of 4-nitrobenzyl 4-ethylthioacetoacetate,which was obtained in Reference Example 14, was used in place of methyl4-methoxyacetoacetate, there was obtained the above-mentioned desiredcompound.

Melting point: 207-210° C.; ¹H-NMR (CDCl₃) δ: 1.26 (t, J=7.3 Hz, 3H),2.55 (q, J=7.3 Hz, 2H), 3.78 (s, 2H), 5.80 (s, 1H), 7.29-7.37 (m, 9H),7.96 (s, 1H), 9.97 (brs, 1H).

Example 31

[Synthesis of4,7-dihydro-7-oxo-3-(4-phenylthiophenyl)-5-(2-pyridylthiomethyl)pyrazolo[1,5-a]pyrimidine]

Reactions were carried out similar to those of used in Example 1, exceptthat the same molar quantity of ethyl 4-(2-pyridylthio)acetoacetate,which was obtained in Reference Example 24, was used in place of methyl4-methoxyacetoacetate, there was obtained the above-mentioned desiredcompound.

Melting point: 222-224° C.; ¹H-NMR (DMSO-d₆) δ: 4.40 (s, 2H), 5.89 (s,1H), 7.17 (dd, J=5 Hz, 7 Hz, 1H), 7.31-7.45 (m, 8H), 7.57 (d, J=8.25 Hz,2H), 7.71 (dt, J=2 Hz, 8 Hz, 1H), 8.18 (s, 1H), 8.44 (d, J=5 Hz, 1H),12.2 (brs, 1H).

Example 32

[Synthesis of4,7-dihydro-5-(2-methylthioethyl)-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine]

Reactions were carried out similar to those of used in Example 1, exceptthat the same molar quantity of 4-nitrobenzyl5-methylthio-3-oxopentanate, which was obtained in Reference Example 15,was used in place of methyl 4-methoxyacetoacetate, there was obtainedthe above-mentioned desired compound.

Melting point: 202-204° C.; ¹H-NMR (DMSO-d₆) δ: 2.12 (s, 3H), 2.83-2.91(m, 4H), 5.79 (s, 1H), 7.33-7.42 (m, 7H), 7.58 (d, J=7.59 Hz, 2H), 8.14(s, 1H), 11.8 (brs. 1H).

Example 33

[Synthesis of4,7-dihydro-7-oxo-3-(4-phenylthiophenyl)-5-[2-(2-pyridylthio)ethyl]pyrazolo[1,5-a]pyrimidine]

Reactions were carried out similar to those of used in Example 1, exceptthat the same molar quantity of 4-nitrobenzyl5-(2-pyridylthio)-3-oxopentanate, which was obtained in ReferenceExample 16, was used in place of methyl 4-methoxyacetoacetate, there wasobtained the above-mentioned desired compound.

Melting point: 193-197° C.; ¹H-NMR (DMSO-d₆) δ: 3.03 (t, J=7 Hz, 2H),3.53 (t, J=7 Hz, 2H), 5.74 (s, 1H), 7.06-7.11 (m, 1H), 7.30-7.42 (m,8H), 7.57-7.65 (m, 3H), 8.14 (s, 1H), 8.38 (d, J=4.65 Hz, 1H), 11.9(brs, 1H).

Example 34

[Synthesis of4,7-dihydro-5-(3-ethylthiopropyl)-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine]

Reactions were carried out similar to those of used in Example 1, exceptthat the same molar quantity of 4-nitrobenzyl 6-ethylthio-3-oxohexanate,which was obtained in Reference Example 17, was used in place of methyl4-methoxyacetoacetate, there was obtained the above-mentioned desiredcompound.

Melting point: 173-176° C.; ¹H-NMR (CDCl₃) δ: 1.17 (t, J=7.3 Hz, 3H),2.06 (m, 2H), 2.46 (q, J=7.3 Hz, 2H), 2.61 (t, J=7 Hz, 2H), 2.87 (t, J=7Hz, 2H), 5.66 (s, 1H), 7.17-7.32 (m, 9H), 7.83 (s, 1H), 10.7 (brs, 1H).

Example 35

[Synthesis of sodium5-methoxymethyl-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidin-7-olate]

4,7-Dihydro-5-methoxymethyl-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine(0.98 g), which was obtained in Example 1, was dissolved in ethylalcohol (20 ml) and an aqueous solution of 1N-sodium hydroxide (2.7 ml),then the solution was concentrated under reduced pressure, the residuethus obtained was dried, there was obtained the above-mentioned desiredcompound (1.04 g).

Melting point: 206-209° C.; ¹H-NMR (DMSO-d₆) δ: 3.36 (s, 3H), 4.31 (s,2H), 5.66 (s, 1H), 7.20-7.40 (m, 7H), 8.19-8.22 (m, 3H).

Example 36

[Synthesis of4,7-dihydro-5-methoxymethyl-3-(3-methyl-4-phenylthiophenyl)-7-oxopyrazolo[1,5-a]pyrimidine]

Reactions were carried out similar to those of used in Example 5, exceptthat methyl 4-methoxyacetate was used in place of ethyl4-isopropoxyacetate, and the same molar quantity of3-amino-4-(3-methyl-4-phenylthiophenyl)pyrazole, which was disclosed inWO 92/06096, was used in place of3-amino-4-(4-phenylthiophenyl)pyrazole, there was obtained theabove-mentioned desired compound.

Melting point: 151-157° C.; ¹H-NMR (CDCl₃) δ: 2.42 (s, 3H), 3.53 (s,3H), 4.50 (s, 2H), 5.76 (s, 1H), 7.17 (d, J=7.6 Hz, 1H), 7.22-7.35 (m,7H), 8.02 (s, 1H), 9.16 (brs, 1H).

Example 37

[Synthesis of4,7-dihydro-5-methoxymethyl-3-(3-methoxy-4-phenylthiophenyl)-7-oxopyrazolo[1,5-a]pyrimidine]

Reactions were carried out similar to those of used in Example 1, exceptthat the same molar quantity of3-amino-4-(3-methoxy-4-phenylthiophenyl)pyrazole, which was disclosed inWO 92/06096, was used in place of3-amino-4-(4-phenylthiophenyl)pyrazole, there was obtained theabove-mentioned desired compound.

Melting point: 194-197° C.; ¹H-NMR (CDCl₃) δ: 3.52 (s, 3H), 3.91 (s,3H), 4.52 (s, 2H), 5.75 (s, 1H), 6.85-6.91 (m, 2H), 7.06 (d, J=7.6 Hz,1H), 7.26-7.40 (m, 5H), 7.98 (s, 1H), 9.44 (brs, 1H).

Example 38

[Synthesis of4,7-dihydro-5-(3-methylphenoxymethyl)-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine]

Reactions were carried out similar to those of used in Example 1, exceptthat the same molar quantity of ethyl 4-(3-methylphenoxy)acetoacetate,which was obtained in Reference Example 25, was used in place of methyl4-methoxyacetoacetate, there was obtained the above-mentioned desiredcompound.

Melting point: 188-190° C.; ¹H-NMR (CDCl₃) δ: 2.31 (s, 3H), 5.18 (s,2H), 5.92 (s, 1H), 6.75-6.85 (m, 3H), 7.14-7.28 (m, 10H), 7.85 (s, 1H),10.7 (brs, 1H).

Example 39

[Synthesis of4,7-dihydro-7-oxo-3-(4-phenylthiophenyl)-5-(3-trifluoromethylphenoxymethyl)pyrazolo[1,5-a]pyrimidine]

Reactions were carried out similar to those of used in Example 5, exceptthat the same molar quantity of ethyl4-(3-trifluoromethylphenoxy)acetoacetate, which was obtained inReference Example 26, was used in place of ethyl4-isopropoxyacetoacetate, there was obtained the above-mentioned desiredcompound.

Melting point: 173-176° C.; ¹H-NMR (CDCl₃) δ: 5.29 (brs, 1H), 5.95 (brs,1H), 7.10-7.42 (m, 13H), 7.78 (brs, 1H), 11.4 (brs, 1H).

Example 40

[Synthesis of4,7-dihydro-5-(3-methoxyphenoxymethyl)-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine]

Reactions were carried out similar to those of used in Example 1, exceptthat the same molar quantity of 4-(3-methoxyphenoxy)acetoacetate, whichwas obtained in Reference Example 27, was used in place of methyl4-methoxyacetoacetate, there was obtained the above-mentioned desiredcompound.

Melting point: 191-194° C.; ¹H-NMR (CDCl₃) δ: 3.76 (s, 3H), 5.17 (s,2H), 5.92 (s, 1H), 6.53-6.58 (m, 3H), 7.16-7.28 (m, 10H), 7.86 (s, 10H),10.6 (br, 1H).

Example 41

[Synthesis of5-(4-carboxyphenoxymethyl)-4,7-dihydro-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine]

Reactions were carried out similar to those of used in Example 1, exceptthat the same molar quantity of ethyl 4-(4-carboxyphenoxy)acetoacetate,which was obtained in Reference Example 28, was used in place of methyl4-methoxyacetoacetate, there was obtained the above-mentioned desiredcompound.

Melting point: >300° C. (decomposed); ¹H-NMR (CDCl₃) δ: 5.19 (s, 2H),5.93 (s, 1H), 7.13 (d, J=8 Hz, 2H), 7.30-7.44 (m, 7H), 7.61 (d, J=8 Hz,2H), 7.93 (d, J=8 Hz, 2H), 8.21 (s, 1H), 12.2 (brs, 1H), 12.7 (br, 1H).

Example 42

[Synthesis of2,5-bis(methoxymethyl)-4,7-dihydro-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1,5-a]-pyrimidine]

Reactions were carried out similar to those of used in Example 1, exceptthat the same molar quantity of3-amino-5-methoxymethyl-4-(4-phenylthiophenyl)pyrazole, which wasdisclosed in WO 92/06096, was used in place of3-amino-4-(4-phenylthiophenyl)pyrazole, there was obtained theabove-mentioned desired compound.

Melting point: 192-198° C.; ¹H-NMR (CDCl₃) δ: 3.38 (s, 3H), 3.50 (s,3H), 4.47 (s, 2H), 4.55 (s, 2H), 5.74 (s, 1H), 7.32-7.46 (m, 9H), 9.05(brs, 1H).

The present invention will be explained more specifically by showingPharmacological Tests and Preparation Examples below.

PHARMACOLOGICAL TESTS Test Example 1

[Evaluation test of activity for inhibiting the formation of NO]

Pharmacological tests of pyrimidine derivatives obtained in Examples 1,12, 14, 19, 22, 24, 29 and 42 used as test compounds were conducted asfollows.

Preparation of culture media and method of cell culture were conductedin accordance with those described in J. Biol. Chem., Vol. 269, No. 1,pp. 711-715, (1994), and determination of formed amount of NO wasconducted in accordance with the method described in Anal. Biochem.,Vol. 126, pp. 131-138, (1982), respectively.

(1) Cell Culture and Inducible Synthesis of NO in the Cells byStimulation with Lipopolysaccharide (LPS)

Cell strain RAW 264.7 (ATCC) derived from the macrophage of mouse wasplaced on each one of the wells on a microplate having 24-wells so as toput the cells in an amount of 1×10⁵ cells/U (well). The cells wereincubated for 24 hours in a phenol red free-RPMI-1640 culture medium(mfd. by GIBCO) to which 10% of fetal bovine serum, 100 U/ml ofpenicillin (mfd. by Dainippon Pharmaceutical Co., Ltd.) and 100 μg/ml ofstreptomycin (mfd. by Dainippon Pharmaceutical Co., Ltd.) were added.

Next, the reference culture medium was prepared by adding 2 mM ofL-arginine (mfd. by Wako Pure Chemical Industries, Ltd.), 10 μM/ml oftetrahydrobiopterin (mfd. by ALEXIS) and 100 ng/ml of lipopolysaccharide(LPS)(mfd. by Sigma Chemical Co.) to a phenol red free-RPMI-1640 culturemedium. While, the reference culture medium without containing LPS wasused as the blanc culture medium.

On the other hand, the test culture medium, containing the test compoundwas prepared by adding 0.2% of the test compounds dissolved in dimethylsulfoxide (DMSO) to the reference culture medium to adjust the finalconcentration of the test compound to 1×10⁻⁶ M.

Each one of the blank culture medium, reference culture medium and testculture medium containing the test compound was added, respectively tothe well on the micro-plate where the above-mentioned cell strain RAW264.7 was placed, and was incubated for 24 hours.

(2) Measurement of the Amount of Formed NO

Quantitative measurement of NO cannot be made directly, due to itsunstability. Therefore, the amount of NO is measured indirectly, thus byforming nitrous acid ion (hereunder referred to as NO₂ ⁻) which isstable product derived from NO by use of Griess reagent [consisting of1% of sulfanylamide and 0.1% of sulfuric acid solution containing 0.1%N-(1-naphthyl)ethylenediamine dihydrochloride], and measure the amountof NO₂ ⁻.

Into the supernatant of each one of the culture media was admixed withthe same amount of Griess reagent respectively, and subjected toreaction at room temperature for 10 minutes, then the optical absorbanceat 540 nm of the thus reacted culture medium was measured. While, theoptical absorbance of sodium nitrite solution diluted with the culturemedium was referred to as the standard value, and the amount of NO₂ ⁻formed in each one of these incubated culture media was measured. Theamounts of NO₂ ⁻ formed in the reference culture medium and the testculture medium were corrected by using the value of formed amount of NO₂⁻ in the blanc culture medium.

On the basis of that the ratio of amounts of NO₂ ⁻ formed in thereference culture medium and that of formed in the test culture mediumis corresponding to the ratio of amount of NO formed in the referenceculture medium and that of formed in the test culture medium. Thus theamount of NO₂ ⁻ formed in the reference culture medium is referred to asthe value of 100, and the value of amount of NO₂ ⁻ formed in the testculture medium is referred to as amount of NO formed in the test culturemedium. The results are shown in the following Table 1.

TABLE 1 Ratio of formed Test compound amount of NO (%) (*) Example 156.0 Example 12 67.0 Example 14 64.4 Example 19 63.1 Example 22 60.3Example 24 67.3 Example 29 52.2 Example 42 55.4 (*) Measured at theconcentration of 1 × 10⁻⁶ M of the test compound.

Test Example 2

[Toxicity test (Toxicity of compound against the cell strain RAW 264.7)]

Test was conducted in accordance with the method as described in J.Immunol. Methods, Vol. 94, pp. 57-68, (1986). Cell strain RAW 264.7derived from the macrophage of mouse was incubated similarly as in themethod of Test Example 1(1). After that, MTT reagent (5 mg/ml) in 1/10amount of the culture medium was added to the cells, and incubated for 4hours. The supernatant of culture medium was taken off, then the cellswere collected by using 1% SDS solution and the optical absorbance at570-630 nm of the SDS solution was measured. The results are shown inthe following Table 2.

TABLE 2 Ratio of optical Test compound absorbance (%) (**) Example 1 108.9 Example 12 102.8 Example 14  94.2 Example 22 101.2 Example 24107.7 Example 29  89.7 (**) Measured at the concentration of 1 × 10⁻⁶ Mof the test compound.

Test Example 3

[Model experiment of asthma in guinea pigs. (Inhibition of lateasthmatic response)]

Test was conducted by the method described in J. Pharmacol. Exp. Ther.,Vol. 277, pp. 1622-1629, (1996).

Hartley strain female guinea pigs (SLC) having the body weight of about350 g were used and 50 mg/Kg of cyclophosphamide (mfd. by Sigma ChemicalCo.) was injected intraperitoneally. 2 Days after this pretreatment byinjection, 1 mg of egg albumin (mfd. by Sigma Chemical Co.) and 100 mgof aluminum hydroxide (Wako Pure Chemical Industries Co., Ltd.) wereinjected intraperitoneally for sensitization. 3 Weeks after thesensitization, 10 μg of egg albumin and 100 mg of aluminum hydroxidewere injected intraperitoneally for booster sensitization. 6 Weeks afterthe primary sensitization, asthma attach was induced by inhalation andexposure to egg albumin (4 mg/ml) by using a nebulizer (NE-U12: mfd. byOmron Corp.). The asthma reaction was determined by use of abody-plethysmography (using system developed by Uchida lecturer ininternal department for respiratory organs at Tsukuba University;air-resist tube, respiratory amplifier and differential pressuretransducer (mfd. by Nihon Koden); and osciloscope (mfd. by IwasakiTsushin)), so as to determine a drug of specific airway conductance(sGaw) under the condition without anesthesia. The sGaw value justbefore the administration of test comopound was measured and the valueis referred to as 100. Test compound was suspended in 1% HPMC(hydroxymethylpropylcellulose mfd. by Shinetsu Chemical), and wasadministered orally 30 minutes before the exposure with the antigen.Then, sGaw value was measured in each points until 7 hours after theexposure with the antigen. Effect of the test compound was evaluatedfrom the area under curve (AUC) of sGaw reaction induced by the exposurewith the antigen during 4-7 hours. The results are shown in thefollowing Table 3.

TABLE 3 Test compound Number of test AUC (mg/Kg of body weight) animals(4-7 hours) Control (10) 6   112 ± 17.8 Compound of Example 1 (10) 632.8 ± 9.2 Prednizolone (30) 8 15.6 ± 3.5 7-Hydroxy-3-(4-phenylthio-(39) 3 127.9 ± 45.4 phenyl)pyrazolo[1,5-a]- pyrimidine (Exp. 3 ofJP-A-5-112571)

Test Example 4

[Contact hypersensitivity model in mouse (Atopic dermatisis model)]

Test was conducted by referring to the method as described in “HIFU (aJapanese journal of dermatology)” Vol. 35, Supplemental Issue No. 15,pp. 96-106, published on March 1993.

CBA/J strain mice of 6-8 week age were used as the test animals (6-8mice in one group). The mouse was sensitized by coating 150 μl of 5% ofpicryl chloride [dissolved in a mixture of acetone with olive oil (1:4)]on the shaved portion of skin in the back of mouse. 4 Days after thesensitization, contact hypersensitivity was causally induced by coating0.8%, 5% of picryl chloride [dissolved in a mixture of acetone witholive oil (1:4)] on the left-pinna of the mouse. 24 Hours after thecausal induction, the effect for inhibiting contact hypersensitivityperformed by the test compounds were evaluated by referring to theaction for inhibiting intumescence of the pinna as an indication. Thetest compound was orally administered 30 minutes before the causalinduction.

The following compounds were used for the test.

1) Compounds of the Present Invention:

(1) Compound of Example 1 (Dosage: 2 mg/Kg p.o.)

(2) Compound of Example 15 (Dosage: 3 mg/Kg p.o.)

(3) Compound of Example 19 (Dosage: 3 mg/Kg p.o.)

2) Comparative Compounds

(Dosage: 20 mg/Kg p.o., which is 7-10 times larger amount of dosages forcompounds of the present invention)

(1)7-Hydroxy-5-cyclopropyl-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine(Example 8 of JP-A-5-112571 and Example 7 of WO97/11946)

(2) 7-Hydroxy-5-methyl-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine(Example 5 of JP-A-5-112571)

(3)7-Hydroxy-2-methoxymethyl-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine(Example 19 of JP-A-5-112571)

(4) 7-Hydroxy-5-chloromethyl-2-phenylpyrazolo[1,5-a]pyrimidine (Example29 of WO97/11946)

(5) 7-Hydroxy-3-(3-trifluoromethylphenyl)pyrazolo [1,5-a]pyrimidine(Example 27 of WO97/11946)

(6)7-Hydroxy-5-methyl-3-(3-methoxy-4-phenylthiophenyl)-2-(2-pyridyl)pyrazolo[1,5-a]pyrimidine(Example 31 of WO97/11946)

(7)7-Hydroxy-5-chloromethyl-2-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine(Example 33 of WO97/11946)

(8) 7-Hydroxy-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine (Example 3of JP-A-5-112571)

The value obtained from the sensitization test without administration ofthe test compound was referred to as 100, and by comparing with thevalues obtained from the sensitization test with administration of thetest compound was referred to “% control” values. The results are shownin the following Table 4.

TABLE 4 Test compound Control % 1) Compound of the present invention (1)53.7 (2) 46.3 (3) 44.7 2) Comparative compounds (1) 99.0 (2) 90.0 (3)104.2 (4) 102.6 (5) 90.4 (6) 94.7 (7) 113.0 (8) 100.0

Test Example 5

[Evaluation test of activity for inhibiting the formation of TNF-α invitro]

Pyrimidine derivative obtained in Example 1 was used as test compound.

Cell strain RAW 264.7 (ATCC) derived from the macrophage of mouse wasplaced on each one of the wells on a microplate having 24-wells so as toput the cells in an amount of 3×10⁵ cells/U (well). The cells wereincubated for 24 hours in a phenol red free-RPMI-1640 culture medium(mfd. by GIBCO) to which 10% of equine serum (mfd. by Bio Whittaker),100 U/ml of penicillin (mfd. by Dainippon Pharmaceutical Co., Ltd.) and100 μg/ml of streptomycin (mfd. by Dainippon Pharmaceutical Co., Ltd.)were added.

Next, the equine serum was removed from the culture medium, and thereference culture medium as control was prepared by adding 2 mM ofL-arginine (mfd. by Wako Pure Chemical Industries, Ltd.), 10 μM/ml oftetrahydrobiopterin (mfd. by ALEXIS) and 100 ng/ml of lipopolysaccharide(LPS)(mfd. by Sigma Chemical Co.) to a phenol red free-RPMI-1640 culturemedium, so as to induce the formation of TNF-α.

On the other hand, the test culture medium, containing the test compoundof Example 1 was prepared similarly as in the reference culture medium,except adding the test compound (1×10⁻⁴, 1×10⁻⁵ and 1×10⁻⁶ M) dissolvedin dimethyl sulfoxide (DMSO) at the same time of LPS-addition.

The concentration of TNF-α formed in the supernatant of each one of theculture media after 24 hour-incubation was measured by Factor-Test-XMouse TNF-α ELISA Kit (mfd. by genzyme). The results are shown in thefollowing Table 5.

TABLE 5 Ratio of formed Test compound Concentration (M) amount of TNF-α(%) Control — 100 Example 1 1 × 10⁻⁶ 120.0 ″ 1 × 10⁻⁵ 59.9 ″ 1 × 10⁻⁴5.1

Test Example 6

[Evaluation test of activity for inhibiting the formation of IL-8 invitro]

Pyrimidine derivative obtained in Example 1 was used as test comppound.

Cell strain A 549 (ATCC) derived from human alveolar epithelium cellswas placed on each one of the wells on a microplate having 24-wells soas to put the cells in an amount of 3×10⁵ cells/U (well). The cells wereincubated for 24 hours in F-12 Nutrient Mixture culture medium (mfd. byGIBCO) to which 10% of equine serum, 100 U/ml of penicillin (mfd. byDainippon Pharmaceutical Co., Ltd.) and 100 μg/ml of streptomycin (mfd.by Dainippon Pharmaceutical Co., Ltd.) were added.

Next, the equine serum was removed from the culture medium, and thereference culture medium as control was prepared by adding inducers ofTNF-α (mfd. by genzyme), IL-1β (mfd. by genzyme) and IFN-γ (mfd. bygenzyme) to the culture medium, so as to induce the formation of IL-8.

On the other hand, the test culture medium, containing the test compoundof Example 1 was prepared similarly as in the reference culture medium,except adding the test compound (1×10⁻⁵, 1×10⁻⁶ and 1×10⁻⁷ M) dissolvedin dimethyl sulfoxide (DMSO) at the same time of inducers-addition.

The concentration of IL-8 formed in the supernatant of each one of theculture media after 24-hour incubation was measured by IL-8 ELISA KitHuman (mfd. by genzyme). Further, MTT assay was conducted by the similarmethod as described in Text Example 2 to determine the index of toxicityfor cells. The results are shown in the following Table 6.

TABLE 6 Ratio of Test Concentration Ratio of formed optical compound (M)amount of IL-8 (%) absorbance (%) Control — 100.0 100.0 Example 1 1 ×10⁻⁷ 64.5 108.2 ″ 1 × 10⁻⁶ 52.6 98.1 ″ 1 × 10⁻⁵ 13.4 126.5

Test Example 7

[Evaluation test of activity for inhibiting 5-lipoxygenase in vitro]

Pyrimidine derivative obtained in Example 1 was used as test compound.

Test was referred to the methods as described in Proc. Natl. Acad. Sci.U.S.A., Vol. 81, pp. 689-693 (1984) and J. Biol. Chem., Vol. 260, pp.11554--11559 (1985).

(1) Preparation of Crude Enzyme Containing 5-lipoxygenase

RBI-1 cells (rat basophilic leukemia-1, ATCC, 1×10⁸ cells) in 5 ml ofbuffer solution (50 mM Tris/1 mM EDTA, pH 7.4) were lysed with nitrogencavitation bomb (mfd. by PARR Instrument Company) under 750 psi for 20min at 4° C. The solution were centrifuged with twice volume of 50 mMTris/1 mM EDTA (pH 7.4) at 5000 rpm for 10 minutes at 4° C. Thesupernatant of the solution was taken and further centrifuged at 37,500rpm for 90 minutes at 4° C. Thus obtained supernatant was collected andconcentrated so as to obtain crude enzyme containing 5-lipoxygenase. Itsprotein concentration was determined with Protein assey kit (mfd. byPierce).

(2) Evaluation of Activity for Inhibiting 5-lipoxygenase (RIA assay)

12.5 μl of Crude enzyme, 61.5 μl of 50 mM Tris-HCl (mfd. by SigmaChemical Co.), 12.5 μl of 0.5 mM ATP (mfd. by Sigma Chemical Co.), and12.5 μl of cofacter solution (50 mM Tris-HCl (pH 7.2, at 25° C.)containing 10 mM glutahion, 14 mM of indomethacin and 500 mM ofCaCl₂.2H₂O) were preincubated for minutes at 25° C. for referencesolution as control. On the other hand, the test solution containing thetest compound of Example 1 was prepared similarly as in the referencesolution, except adding 1 μl of the test compound (1×10⁻⁴, 1×10⁻⁵, and1×10⁻⁶ M).

25 μl of 0.07 mM Arachidonic acid (mfd. by Sigma Chemical Co.) was addedeach of the reference solution and test solutin to intiate the reaction,and incubated it for 8 minutes at 25° C. The reaction was terminated byadding 40 μl of citric acid (mfd. by Sigma Chemical Co.). 350 μl of 0.11M Butylated hydroxytoluene solution (in 50 mM of Tris-HCl, pH 8.5) wasadded thereto and each of the mixed solutions were stirred vigorously.

RIA assay was conducted by the 5-HETE [³H] RIA assay kit (mfd. byPerSeptive Biosystems) according to its instructions. 7 μl of each mixedsolutions were used as reaction solution for 5-HETE [³H] RIA assay todetermine the amount of 5-lipoxygenase by counting radioactivity on theliquid scintillation counter (mfd. by Beckman Co.).

The value obtained from the reference solution as control was comparedwith that of the test solutions by the rate of “%inhibition”. Theresults are shown in the following Table 7.

TABLE 7 Test Concentration compound (M) % Inhibition Example 1 1 × 10⁻⁶68.0 ″ 1 × 10⁻⁵ 38.8 ″ 1 × 10⁻⁴ 24.3

Preparation Example 1

4,7-Dihydro-5-methoxymethyl-7- 150 g oxo-3-(4-phenylthiophenyl)-pyrazolo[1,5-a]pyrimidine Avicel (trade name for microcrystalline 40 gcellulose, manufactured by Asahi Chemical Industry Co., Ltd.) Cornstarch 30 g Magnesium stearate 2 g Hydroxypropylmethyl cellulose 10 gPolyethylene glycol 6000 3 g Castor oil 40 g Methanol 40 g

4,7-Dihydro-5-methoxymethyl-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine,Avicel, corn starch and magnesium stearate were mixed together andground, then the mixture was shaped into the form of tables by using aconventional pounder (R 10 mm) for sugar coating. The tablets werecoated with a film-coating agent consisting of hydroxypropylmethylcellulose, propylene glycol 6000, caster oil and methanol, to preparefilm-coated tablets.

Preparation Example 2

4,7-Dihydro-5-methoxymethyl-7- 150.0 goxo-3-(4-phenylthiopheyl)pyrazolo- [1,5-a]pyrimidine Citric acid 1.0 gLactose 33.5 g Dicalcium phosphate 70.0 g Pluronic F-68 30.0 g Sodiumlauryl sulfate 15.0 g Polyvinyl pyrrolidone 15.0 g Polyethylene glycol(Carbowax 1500) 4.5 g Polyethylene glycol (Carbowax 6000) 45.0 g Cornstarch 30.0 g Dry sodium lauryl sulfate 3.0 g Dry magnesium stearate 3.0g Ethanol A sufficient quantity

4,7-Dihydro-5-methoxymethyl-7-oxo-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine,citric acid, lactose, dicalcium phosphate, Pluronic F-68 and sodiumlauryl sulfate were mixed together.

The mixture was sieved through a No. 60 screen. The resulting sievedmixture was wet-granulated with an ethanol solution containing polyvinylpyrrolidone, Carbowax 1500 and Carbowax 6000. In case of necessity,ethanol was added to convert the mixture into a paste-like mass. Cornstarch was added, and mixing operation was contiued until uniformparticles were formed. The resulting particles were passed through a No.10 screen, then placed in a tray, and were dried in an oven at 100° C.for 12-14 hours. The dried particles were sieved through a No. 16screen. Next, dry sodium lauryl sulfate and dry magnesium stearate wereadded to the resulting particles. The mixture was compressed into coretablets of the desired shape by using a tablet machine.

The resulting core tablets were treated with a varnish and then talc wassprayed thereon for preventing from moisture absorption. On the surfaceof resulting core tablets, undercoat layer was coated. Sufficient numberof varnish coatings were conducted to the core tablets so as to makethem suitable for internal use. Formation of undercoat layer and smoothcoating were conducted to make the coated tablets having completelyround and smooth surface. Color coating was conducted until the desiredcolor surface was obtained. After drying, the coated tablets werepolished to obtain tablets of uniform gloss.

Preparation Example 3

4,7-Dihydro-5-methoxymethyl-7- 5.0 g oxo-3-(4-phenylthiophenyl)-pyrazolo[1,5-a]pyrimidine Polyethylene glycol (mol. wt.: 4000) 0.3 gSodium chloride 0.9 g Polyoxyethylene sorbitan monooleate 0.4 g Sodiummetabisulfite 0.1 g Methylparaben 0.18 g Propylparaben 0.02 g Distilledwater for injection 10.0 ml

Parabens, sodium metabisulfite and sodium chloride were dissolved in ahalf volume of the above mentioned distilled water for injection at 80°C. under stirring. The resulting solution was cooled to 40° C., then tothis solution was added4,7-dihydro-5-methoxymethyl-7-oxo-3-(4-phenylthiophenyl)pyrazole[1,5-a]pyrimidine,polyethylene glycol and polyoxyethylene sorbitan monooleate and weredissolved. Next, to the resulting solution was added the remaining ahalf volume of the distilled water to make the solution to the finalvolume. Thus obtained solution was sterilized by passing through asuitable filter paper, to prepare the desired injection preparation.

What is claimed is:
 1. A compound represented by the formula (1),

wherein R represents a group of the formula,

 wherein R¹ and R² are a hydrogen atom; R³ is a methyl group and A is anoxygen atom and R⁴ and R⁸ a hydrogen atom, or pharmaceuticallyacceptable salt thereof.
 2. A method for treating an allergic disease byadministering to a patient in need thereof an agent comprising, as theeffective ingredient, a compound represented by the formula (1) orpharmaceutically acceptable salt thereof as claimed in claim
 1. 3. Amethod for treating asthma by administering to a patient in need thereofan agent comprising, as the effective ingredient, a compound representedby the formula (1) or pharmaceutically acceptable salt thereof asclaimed in claim
 1. 4. A method for treating an atopic dermatitis, byadministering to a patient in need thereof an agent comprising, as theeffective ingredient, a compound represented by the formula (1) orpharmaceutically acceptable salt thereof as claimed in claim
 1. 5. Amethod for treating an allergic disease, by administering to a patientin need thereof an agent comprising, as the effective ingredient, acompound represented by the formula (1),

wherein R represents a group of the formula,

 wherein R¹ is a hydrogen atom or a lower alkyl group; R² is a hydrogenatom or a lower alkoxy group; R³ is a hydrogen atom, an alkyl group, alower alkanoyl group, a phenyl group which may have substituentsselected from the group consisting of a lower alkoxy group, a carboxylgroup, a halogen substituted-lower alkyl group and a lower alkyl group,an aralkyl group, a tetrahydropyranyl group, a pyridyl group, acycloalkyl group, a hydroxy-lower alkyl group, and a lower alkoxy-loweralkyl group; A is an oxygen atom or sulfur atom; further R² and R³ maybe combined to each other to form a tetrahydrofuranyl group ortetrahydropyranyl group; n is 0-2; R⁴ is a hydrogen atom, a lower alkylgroup or a lower alkoxy group; R⁸ is a hydrogen atom, a lower alkylgroup or a lower alkoxy-lower alkyl group, or pharmaceuticallyacceptable salt thereof.
 6. The method for treating an allergic diseaseof claim 5, wherein the allergic disease is asthma.
 7. The method fortreating an allergic disease of claim 5, wherein the allergic disease isatopic dermatitis.